book of abstracts medchem2019 catanzaromedchem2019.unicz.it/book_of_abstracts_medchem2019... ·...

MedChem19 Catanzaro

BOOK OF ABSTRACTS IV annual COST ACTION CA15135 meeting

Paul Ehrlich Euro-PhD Network & MuTaLig COST Action meeting 2019

Complesso Monumentale San Giovanni Catanzaro (Italy), June 13th-15th 2019

www.pehrlichmedchem.eu www.mutalig.eu

medchem2019.unicz.it

BOOK of ABSTRACTS

MedChem2019

Paul Ehrlich Euro-PhD Network &

MuTaLig COST Action meeting

Catanzaro (Italy), June 13th

-15th

2019

1

WELCOME PREFACE

Organizing Committee of this event is glad to welcome all participants to

this joint meeting between the Paul Ehrlich Euro-PhD Network and the MuTaLig

COST Action. There are special links among these two Medicinal Chemistry

international initiatives at least due a couple of relevant issues.

The first one regards their interest to train highly-specialized young

investigators in Medicinal Chemistry area. The Paul Ehrlich Euro-PhD Network

releases a special label for curricula demonstrating to be excellent during the

doctorial period. MuTaLig, as all COST Actions from 1971, promotes the excellence

among young investigators with specific mobility tools, such as STSM and ITC

grants.

The second issue is the cooperation among pan-European countries. The

current number of adhering universities and parties to the Paul Ehrlich Euro-PhD

Network and to the MuTaLig COST Action is respectively higher than 50 and 30.

Many participants belong to both Medicinal Chemistry consortia and some are

also affiliated to private institutions. So, they represent a consistent scientific

critical mass interested to collaborate for the development of novel bioactive tools

against complexes diseases, such as cancer, neurodegenerations or infections.

Among the approaches carried out to perform the drug discovery of new drugs the

emergent multi-targeting paradigm one plays a special role. This is the focus of the

MuTaLig COST Action and involves many members of the Paul Ehrlich Euro-PhD

Network too.

So it appeared very appropriate to put together both scientific communities

in this joint meeting that will be also the occasion to celebrate the first decennial

of the Paul Ehrlich Euro-PhD Network, founded in Palermo in 2009. The program is

perfectly balanced with 19 Paul Ehrlich and 19 MuTaLig oral presentation. The first

day is devoted to the celebration of the decennial and the talks of PhD laureates

eligible of the Paul Ehrlich awards. The second day the meeting includes oral talks

in parallel sessions classified in five thematic sessions. A unique multimedia poster

session, in paperless green style, proposes a rapid presentation of 47 contributions

close to three breaks of the meeting. That can be deeply analyzed also

downloading them from the website of the meeting, thus accelerating the

scientific discussion without printing and bringing a lot of paper. Among them best

BOOK of ABSTRACTS

MedChem2019




-15th

2019

2

posters will be voted and awarded in the third day, when a special session

dedicated to funding opportunities of both consortia will be discussed and

analyzed in the concluding part of the meeting.

In order to keep together as much as possible the audience of the meeting a

rich social activity program was organized proposing one event in each of the

three days, two within the conference venue at the Complesso Monumentale San

Giovanni and one at the archeological site of Scolacium in the province of

Catanzaro.

A special thank goes to all collaborators of my research team and the

Net4Science academic spinoff hosted at the Università “Magna Græcia”di

Catanzaro for the organization of this joint meeting, the assistance in the

compilation of this abstract book, the web site creation and maintenance. Finally,

big acknowledgments are dedicated to all public and private institutions, listed in

the following page, who supported us and permitted to setup this event with great

enthusiasm.

Best wishes for a fruitful pan-European Medicinal Chemistry joint meeting in

Catanzaro!

Stefano Alcaro

Università “Magna Græcia” di Catanzaro (Italy)

Coordinator of the Paul Ehrlich Euro-PhD Network

Chair of CA15135 COST Action

Chair of MedChem2019 joint meeting

[email protected]

BOOK of ABSTRACTS

MedChem2019




-15th

2019

3

Supporting Institutions and Companies

BOOK of ABSTRACTS

MedChem2019




-15th

2019

4

Media Partner

BOOK of ABSTRACTS

MedChem2019




-15th

2019

5

Scientific program

Thursday June 13th

2019

13:30 Registration and welcome coffee (cloister)

“Sala delle Arti” 1

st floor

15:00 Introduction to the IX Paul Ehrlich Euro-PhD network meeting Stefano ALCARO (CA15135 Chair and Paul Ehrlich network Coordinator) - UMG di Catanzaro (Italy) Welcome greetings from the authorities Giovambattista DE SARRO Rector of Università “Magna Græcia” di Catanzaro (Italy) Maria PAVIA Director of the Dipartimento di Scienze della Salute - Università “Magna Græcia” di Catanzaro (Italy)

Session PE I – Celebration of the first ten years of the Paul Ehrlich Euro-PhD Network Moderator: Stefano ALCARO, Università “Magna Græcia” di Catanzaro (Italy)

15:30 PE-PL_1 Paul Ehrlich Euro-PhD Network: from 2 to 53 members

Girolamo CIRRINCIONE Università degli Studi di Palermo (Italy)

16:00 PE-PL_2 Development of chemical tools for nucleotide and lipid receptor-like orphan G protein-coupled receptors

Christa E. MÜLLER Rheinische Friedrich-Wilhelms-Universität, Bonn, (Germany)

Session PE II – Paul Ehrlich Euro-PhD Network PhD awarding ceremony Moderator: Serge VAN CALENBERGH, University of Ghent (Belgium)

16:30 PE-SC_1 Computational studies on MAO-B and AChE inhibitors as potential anti-Parkinson's and anti-Alzheimer's agents

Donatella BAGETTA Università “Magna Græcia” di Catanzaro (Italy) – PE awarded

16:45 PE-SC_2 Design and chemical optimization of 3-phenylquinolone derivatives as potent nontuberculous mycobacteria efflux inhibitors

Tommaso FELICETTI University of Perugia (Italy) – PE awarded

17:00 PE-SC_3 PEGylation technology – the second chance for non-bioavailable drug candidates

Carlos FERNANDES University of Porto (Portugal) – PE awarded

17:15 PE-SC_4 Identification of new 4-fluorobenzyl-analogs as tyrosinase inhibitors via computational studies, synthesis and biological evaluation Laura IELO

University of Messina (Italy) – PE awarded

17:30 PE-SC_5 Molecular modeling of epitopes recognized by neoplastic B-cells in Chronic Lymphocytic Leukemia

Antonio LUPIA Università “Magna Græcia” di Catanzaro (Italy) – PE awarded

17:45 PE-SC_6 Design and development of multi-target agents for neurodegenerative diseases (video presentation)

Ester Sofia BENFEITO University of Porto (Portugal) – PE awarded

18:00 Introduction and tour to the ROMANO CARRATELLI Codex exposition at San Giovanni Museum 19:00 Free welcome party at the Complesso Monumentale San Giovanni (cloister)

22:30 Return to hotels (bus shuttle for registered participants)

BOOK of ABSTRACTS

MedChem2019




-15th

2019

6

Friday June 14th

2019 “Sala GISSING” basing floor “Sala delle Arti” 1

st floor

Session PE III – Novel chemical entities Moderator: Athina GERONIKAKI (Greece)

Session MuTaLig I – Anti-neurodegenerative agents Moderator: Fernanda BORGES (Portugal)

9:00 Introduction to IV MuTaLig annual meeting 9:15 PE-SC_7

Pyrido[2,3-d]pyrimidine-7(8H)-ones: synthesis and biomedical applications

José I. BORRELL Universitat Ramon Llull, Barcelona (Spain)

9:15 CA-SC_1 Maintaining the neuro-transmitter pool in degenerating brain: parameters for propargylamine inhibition of monoamine oxidase

Rona R. RAMSAY University of St Andrews (United Kingdom)

9:30 PE-SC_8 Design and Development of New Chemical Concepts via Controlled Generation of Unstable Carbenoids Species

Vittorio PACE University of Vienna (Austria)

9:30 CA-SC_2 Expanding the coumarin toolbox directed at CNS multitargeting agents

Leonardo PISANI University “Aldo Moro”, Bari (Italy)

9:45 PE-SC_9 Lessons from black pepper: moving from one to multitarget-directed ligands by diversity-oriented synthesis

Daniel CHAVARRIA University of Porto (Portugal)

9:45 CA-SC_3 4-(3-Nitrophenyl)thiazol-2-ylhydra-zone derivatives as selective hMAO-B inhibitors: synthesis, bio-logical activity and computational analysis

Giulia ROTONDI Sapienza University, Rome (Italy)

10:00 PE-SC_10 Position-Selective Synthesis and Biological Evaluation of Four Isomeric A-Ring Amino Derivatives of the Alkaloid Luotonin A

Amra IBRIC University of Vienna (Austria)

10:00 CA-SC_4 Probing fluorine-effects in multitarget anti-Alzheimer agents

Mariagrazia RULLO University “Aldo Moro”, Bari (Italy)

10:15 PE-SC_11 Synthesis of Cytotoxic Isoquinolinequinone N-oxides as Multitargeted Agents

Ryan D. KRUSCHEL University College, Cork (Ireland)

10:15 CA-SC_5 Novel Chromane Derivatives for Alzheimer’s Disease

Anthony BURKE University of Évora (Portugal)

10:30 PE-SC_12 Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Silvia BALDUCCI Sapienza University, Rome (Italy)

10:30 CA-SC_6 Looking for the Pharmacophore of Benzopyran MAO-B Inhibitors

Francesco MESITI Università “Magna Græcia” di Catanzaro (Italy)

10:45 Coffee break (cloister)

11:15 Poster session multimedia exposition - small rooms at the basing floor

“Sala GISSING” basing floor “Sala delle Arti” 1

st floor

Session PE IV – Anti-microbial agents Moderator: Danijel KIKELJ (Slovenia)

Session MuTaLig II – Anti-cancer agents Moderator: Eugenio GAUDIO (Switzerland)

11:45 PE-SC_13 Multi-target design of arginase inhibitors for Leishmania

Alfonso T. GARCÍA-SOSA

University of Tartu (Estonia)

11:45 CA-SC_7 Protein-protein interaction studies on thymidylate synthase leads to the identification and characterization of interface inhibitors as anticancer agents.

Maria Paola COSTI University of Modena e Reggio Emilia (Italy)

12:00 PE-SC_14 Synthesis and biological evaluation of 1’-N-homoazanucleosides: discovery of a 5’-methyl-thioadenosine analogue with antitrypanosomal activity

Jakob BOUTON University of Ghent (Belgium)

12:00 CA-SC_8 A candidate multi-targeting approach to block the CD98hc oncoprotein

Francesco TRAPASSO Università “Magna Græcia” di Catanzaro (Italy)

BOOK of ABSTRACTS

MedChem2019




-15th

2019

7

12:15 PE-SC_15 Halogenated phenothiazines targeting the M.

Tuberculosis type II of the NADH dehydrogenase. Maria Giulia NIZI

University of Perugia (Italy)

12:15 CA-SC_9 The untranslated region of the BCL2 gene and its noncanonical secondary structures

Camilla CRISTOFARI University of Padova (Italy)

12:30 PE-SC_16

A target for macrocyclic antifungals: the needle in

the haystack.

Diego FIORUCCI Università di Siena (Italy)

12:30 CA-SC_10 Multi-enzyme inhibitors for the treatment of cancer

Serenella DEPLANO University of Cagliari (Italy)

12:45 PE-SC_17 Design and synthesis of Mycobacterium tuberculosis thymidylate kinase (MtTMPK) inhibitors Yanlin JIAN

University of Ghent (Belgium)

12:45 CA-SC_11 Development of NO-releasing sigma receptor hybrids as anticancer agents

Maria DICHIARA University of Catania (Italy)

13:00 Lunch (cloister)


“Sala GISSING” basing floor “Sala delle Arti” 1

st floor

Session MuTaLig III: Advanced computational methods Moderator: Vittorio LIMONGELLI, USI Lugano (Switzerland) 14:45 CA-SC_12

Computational tools for multi-target drug discovery Hanoch SENDEROWITZ

University of Bar Ilan, Ramat-Gan (Israel)

15:00 Paul Ehrlich Euro-PhD network coordinator meeting

15:00 CA-SC_13 In silico methods for multi-target drug development

Agnieszka A. KACZOR University of Lublin (Poland)

15:15 CA-SC_14 Combined FAAH and COX inhibition by Flurbiprofen amide derivatives for the treatment of pain and inflammation

Federica MORACA University “Federico II”, of Napoli (Italy)

15:30 CA-SC_15 On the inhibition mechanism of glutathione transferase p1 by piperlongumine. Insight from theory.

Mario PREJANÒ Università della Calabria, Rende (Italy)

15:45 CA-SC_16 In silico repurposing of the hexahydrocyclo-penta[c]quinoline scaffold as potent Carbonic Anhydrase inhibitors

Annachiara TINIVELLA University of Modena e Reggio Emilia (Italy)

16:00 Coffee break (cloister)


17:00 Social activity for booked participants only (optional)

BOOK of ABSTRACTS

MedChem2019




-15th

2019

8

Saturday June 15th

2019

“Sala GISSING” basing floor 9:00 Welcome coffee (cloister)

9:30 Best poster voting deadline

9:30 MuTaLig MC meeting (MC members only)

“Sala delle Arti” 1

st floor

Session MuTaLig IV – Opportunities for cooperation research projects Moderator: Maria Laura Bolognesi, Alma Mater Studiorum, University of Bologna (Italy) 10:30 CA-SC_17

Marie Skłodowska-Curie Actions – mobility and training for researchers Frank MARX

Deputy Head of Unit, Research Executive Agency, Bruxelles (Belgium) 10:45 CA-SC_18

The Innovative Medicines Initiative: Europe’s partnership for health Gianluca SBARDELLA

(MC substitute for Italy) University of Salerno (Italy) 11:00 CA-SC_19

Calabria regional policies for research and innovation Menotti LUCCHETTA

Regione Calabria, Catanzaro (Italy) 11:15 CA-SC_20

Exploitation of Research Results: European fund and network Antonio MAZZEI

CalabriaInnova-Fincalabra, Settingiano, Catanzaro (Italy) 11:30 Joint Paul Ehrlich and MuTaLig round table and best poster(s) awarding ceremony Best poster award released by Sharon BRYANT, CEO of Inte:Ligand GmbH, Vienna (Austria) Best poster award released by Rita PODZUNA, Director of Schrödinger GmbH, Mannheim (Germany) Announcements about next Paul Ehrlich and MuTaLig meetings 12:30 Joint Paul Ehrlich and MuTaLig meeting concluding remarks 12:45 Social activity with lunch for booked participants only (optional)

BOOK of ABSTRACTS

MedChem2019




-15th

2019

9

Paul Ehrlich Plenary Lectures

BOOK of ABSTRACTS

MedChem2019




-15th

2019

10

Paul Ehrlich Plenary Lecture 1 (PE-PL_1)

Paul Ehrlich MedChem Euro-PhD Network: from two to fifty-three members Girolamo Cirrincione

Biological, Chemical and Pharmaceutical Sciences and Technologies Department (STEBICEF)

University of Palermo

Email: [email protected]

The seed originating the current Paul Ehrlich PhD network was planted in 2004 thanks to the collaboration of two of our colleagues, Carlo De Micheli (University of Milan) and Peter Matyus (Semmelweis University of Budapest), who organized a joint doctorate course in Medicinal Chemistry which was funded by the European Community. They had the splendid idea of organizing “Annual” meetings with the aim of allowing PhD students in Medicinal Chemistry to share their research experiences and find areas of common interest that would likely lead to fruitful collaborations.

The first meeting was organized by Carlo De Micheli in Milan in October 2004 as a bilateral cooperation between the two involved Universities.

The second edition of the meeting was organized by Peter Matyus in Budapest, in November 2005, and the participation was extended to Palermo and Catania due to already existing bilateral agreements within the ERASMUS Program involving Semmelweis and the two Sicilian Universities.

The third meeting of this series was organized by Giuseppe Ronsisvalle in Catania, in November 2006, and, as before, thanks to ERASMUS cooperation, Universities of Granada and Madrid were invited.

The fourth meeting was held in Granada, organized by Joaquin Campos, in February 2008. In this meeting participants had the opportunity to discuss on the possible synergistic relationship between the Pharmaceutical Industry and the University. In Granada we had two new entries: Universities of Barcelona and Ferrara.

The meeting went back to Milan in its fifth edition, in November 2008, and also in this case two new Universities joint the network: Torino and Novara.

The key event that gave the start to the Paul Ehrlich MedChem Euro-PhD Network took place on June 2009, in Budapest at the Hungarian-Austrian-Czech-German-Greek-Italian-Polish-Slovak-Slovenian 6th Joint Meeting on Medicinal Chemistry, in which Péter Mátyus, Chair of the Conference, in a dedicated session, suggested to establish a PhD medicinal chemistry network among European Universities. All the participants at that session agreed and it was decided to entrust the elaboration of a preliminary document to D. Kikelj, P. Mátyus, G. Ronsisvalle, and G. Cirrincione, who prepared a draft of the rules and conditions for awarding the Paul Ehrlich European PhD in Medicinal Chemistry Label to PhD graduates in Medicinal Chemistry. In the same session it was proposed the first Coordinator of the Network, G. Ronsisvalle, and four components of the Board: B. De Pascual Teresa, N. Haider, D. Kikely and P. Matyus.

Such rules were approved in Palermo, in November 2009 at the 6th Meeting of the European Network of Doctoral Studies in Pharmaceutical Sciences, organized by G. Cirrincione. Thus, the Paul Ehrlich MedChem Euro-PhD Network, was established as a collaboration among 25 European Universities, belonging to 11 different European Countries, with the aim of fostering education and research training of post-graduate students in Medicinal Chemistry, towards PhD degree. The Paul Ehrlich MedChem Euro-PhD Network became active on 1 January 2010 and it was clearly stated that Membership in the network was open to all European Universities while industrial partners and non-EU Academic Institutions could join as associate members.

The 1st Meeting of the Paul Ehrlich MedChem Euro-PhD Network took place in Madrid in July 2011, organized by Universidad de Alcala, Universidad Complutense de Madrid and Universidad San Pablo CEU and the network had 29 members from 14 different European Countries.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

11

The 2nd Meeting was organized by D. Kikelj in September 2012 in Ljubljana, the network had 30 members from 15 European Countries and the first Paul Ehrlich MedChem Euro-PhD certificate was awarded. Since then, year by year, other members joint the network reaching today 53 members from 19 different European Countries and two associate members.

Now, considering the prestige of the Universities belonging to the network and the excellent level of the theses of the PhD who received the Paul Ehrlich MedChem Euro-PhD certificate, in my opinion, it is necessary that the governance of the Network begins the procedure for recognition, by the EFMC.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

12

Paul Ehrlich Plenary Lecture 2 (PE-PL_2)

Development of chemical tools for nucleotide and lipid receptor-like orphan G protein-coupled receptors

Christa E. Müller

Pharmaceutical Institute, Section of Pharmaceutical & Medicinal Chemistry, University of Bonn, Germany


Integral cell membrane proteins such as membrane receptors, in particular G protein-coupled receptors (GPCRs), represent the most important classes of drug targets. With more than 800 members GPCRs constitute the largest protein family in humans. However, only a small percentage of membrane proteins is targeted by current therapies. For about 100 (non-olfactory) GPCRs the endogenous agonist still remains unknown or has been postulated but could not be confirmed (yet). These so-called orphan receptors belong to the most enigmatic members of the GPCR superfamily. In order to study their roles and functions, and for validating them as (potential) novel drug targets, selective agonists and antagonists are required as tool compounds.

Our group has been interested in purinergic and lipid-activated GPCRs, including adenine, adenosine, nucleotide (P2Y), and cannabinoid receptors. Recently, we have extended our focus of interest to closely related orphan GPCRs belonging to the delta-branch of rhodopsin-like GPCRs, e.g. the nucleotide receptor-like GPCRs GPR17 and GPR35, and the cannabinoid receptor-like GPCRs GPR18 and GPR55. Our goal has been to develop potent and selective ligands as biological tools that will allow pharmacological studies of these scarcely investigated orphan receptors. Our strategy includes preparation of stably expressing cell lines, development of suitable functional assays, screening of our compound library consisting of synthetic drug-like compounds and natural products, careful optimization of selected hit compounds by medicinal chemistry approaches including analysis of structure-activity relationships and homology modeling, and preparation of radioligands and fluorescent-labeled ligands (if feasible). Using this approach, we have been successful in developing novel potent and selective ligands as well as multi-target drugs for several orphan GPCRs (for recent examples see [1,2,3]). Potent and selective tool compounds are crucial for elucidating the (patho)physiological roles of GPCRs and for exploring their potential as novel drug targets.

[1] Pillaiyar, T.; Köse, M.; Sylvester, K.; Weighardt, H.; Thimm, D.; Borges, G.; Förster, I.; von Kügelgen, I.; Müller, C.E. J. Med. Chem. 2017, 60 (9), 3636-3655.

[2] Pillaiyar, T.; Köse, M.; Namasivayam, V.; Sylvester, K.; Borges, G.; Thimm, D; von Kügelgen, I.; Müller, C.E. ACS

Omega 2018, 3 (3), 3365-3383.

[3] Schoeder, C.T.; Kaleta, M.; Mahardhika, A.B.; Olejarz-Maciej, A.; Łażewska, D.; Kieć-Kononowicz, K.; Müller, C.E. Eur. J. Med. Chem. 2018, 155, 381-397.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

13

Paul Ehrlich Short Communications

BOOK of ABSTRACTS

MedChem2019




-15th

2019

14

Paul Ehrlich Short Communication 1 (PE-SC_1)

Computational studies on MAO-B and AChE inhibitors as potential anti-Parkinson's and anti-Alzheimer's agents

Donatella Bagettaa,b a Dipartimento di Scienze della Salute, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy

b Net4Science srl, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy


Neurodegenerative pathologies, such as Parkinson's (PD) and Alzheimer's (AD) diseases, are among the most enigmatic and problematic issues in biomedicine. Although each disorder has its own molecular mechanisms and clinical manifestations, some general pathways might be recognized in different pathogenic cascades. Therefore drugs hitting a single target may be moderately effective for the treatment of PD and AD. Conversely, "multi-target-directed ligands” (MTDLs), that could provide real disease-modifying drug candidates, are interesting and remarkably needed [1]. In this scenario, benzopyrone and thiazol-2-ylhydrazone scaffolds were investigated. Both chromone and coumarin [2] derivatives were studied confirming their experimentally known MAO-B selectivity. With the aim to identify MAO-B/AChE dual inhibitors, the chromone scaffold was functionalized at position 2 or 3 with a phenylcarboxamide moiety and at position 6 with a tertiary amine function containing an acrylate substituent (a fragment present in AChE inhibitors) [3]. Molecular docking analysis has described the targets recognition and the reason of the selectivity against MAO-B and AChE isoforms. Finally, new multi-target compounds have been rationally designed, [4] starting from a previously explored thiazol-2-ylhydrazone core.

[1] Bolognesi, M.L.; Cavalli, A. Multitarget drug discovery and polypharmacology. ChemMedChem 2016, 11, 1190-1192.

[2] Fonseca, A.; Reis, J.; Silva, T.; Matos, M.J.; Bagetta, D.; Ortuso, F.; Alcaro, S.; Uriarte, E.; Borges, F. Coumarin versus

Chromone monoamine oxidase B inhibitors: quo vadis? Journal of Medicinal Chemistry 2017, 60, 7206-7212.

[3] Reis, J.; Cagide, F.; Valencia, M.E.; Teixeira, J.; Bagetta, D.; Pérez, C.; Uriarte, E.; Oliveira, P.J.; Ortuso, F.; Alcaro, S.;

Rodríguez-Franco, M.I.; Borges, F. Multi-target-directed ligands for Alzheimer's disease: discovery of chromone-based

monoamine oxidase/cholinesterase inhibitors. European Journal of Medicinal Chemistry 2018, 158, 781-800.

[4] Carradori, S.; Ortuso, F.; Petzer, A.; Bagetta, D.; De Monte, C.; Secci, D.; De Vita, D.; Guglielmi, P.; Zengin, G.;

Aktumsek, A.; Alcaro, S.; Petzer, J.P. Design, synthesis and biochemical evaluation of novel multi-target inhibitors as

potential anti-Parkinson agents. European Journal of Medicinal Chemistry 2018, 143, 1543-1552.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

15


Design and chemical optimization of 3-phenylquinolone derivatives as potent nontuberculous mycobacteria efflux inhibitors

Tommaso Felicetti,a Rolando Cannalire,a Diana Machado,b Andrea Astolfi,a Miguel Viveiros,b Serena Massari,a Oriana Tabarrini,a Maria Letizia Barreca,a Giuseppe Manfroni,a Violetta Cecchetti,a and Stefano

Sabatinia a Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06123-Perugia, Italy

b Unidade de Microbiologia Médica, Universidade NOVA de Lisboa, Rua da Junqueira 100, 1349-008-Lisboa, Portugal


Antimicrobial resistance (AMR) represents a global concern for human health. Nontuberculous mycobacteria (NTM) are ubiquitous microbes belonging to Mycobacterium genus. Among all NTM pathogens, M. avium is one of the most frequent agents causing pulmonary disease, especially in immunocompromised individuals and cystic fibrosis patients. Treatment for M. avium infections consists of a macrolide, such as clarithromycin (CLA), for at least one year, but drug resistance associated to efflux pump (EP) activity often occurs [1]. Thus, identifying non-antibiotic molecules to inhibit the EPs could be a valid alternative to the discovery of new NTM antibacterials.

Given our previous proof that quinoline-based efflux pump inhibitors (EPIs) of the Staphylococcus aureus also inhibit M. avium pumps [2], we herein report the identification of the new 3-phenylquinolone analogues as potent NTM EPIs. After an initial set of 3-phenylquinolone derivatives functionalized by different alkylamino chains on the N-1 position, we obtained potent M. avium EPIs, yet, still suffering from toxicity issues towards human macrophages. As a second step, we started a medicinal chemistry work by designing and synthesizing new 3-phenylquinolone analogues with different substituents on C-6 and C-7 positions. Interestingly, when tested for their NTM EPI activity, two derivatives (1 and 2) showed a strong boosting effect of ciprofloxacin and CLA MICs at doses lower than their CC50 towards human macrophages. Based on these results, we performed ex vivo experiments by testing compound 1 alone and in combination with CLA against M. avium in infected macrophages. Results displayed a significant M. avium survival reduction when compound 1 was tested both alone and with CLA, proving that, regardless of CLA presence, M. avium EPs inhibition in infected macrophages boost the macrophage-mediated killing effect of M. avium.

[1] Rodrigues, L.; Sampaio, D.; Couto, I.; Machado, D.; Kern, W.V.; Amaral, L.; Viveiros, M., J. Antimicrob. Agents 2009,

34, (6), 529-533.

[2] Machado, D.; Cannalire, R.; Costa, S.S.; Manfroni, G.; Tabarrini, O.; Cecchetti, V.; Couto, I.; Viveiros, M.; Sabatini, S., ACS Infect. Dis. 2015 1, (12), 593-603.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

16


PEGylation technology – the second chance for non-bioavailable drug candidates

Carlos Fernandes,a Sofia Benfeito,a Miguel Pinto,a Ricardo Amorim,b José Teixeira,b Cláudia Martins,c,d Bruno Sarmento,c,d Paulo Jorge Oliveira,b Fernando Remião,e Fernanda Borgesa

a CIQUP-Depart. of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal. b CNC-Center for Neuroscience and Cell Biology, UC-Biotech, University of Coimbra, Biocant Park, Cantanhede Portugal

ci3S, Institute of Investigation and Innovation in Health, University of Porto, Porto, Portugal

dINEB, Institute of Biomedical Engineer, University of Porto, Porto, Portugal

eUCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of

Porto, Porto, Portugal.


Central nervous system (CNS) disorders, such neurodegenerative diseases (NDs) are increasing over the last years as a consequence of a continuous growing and aging of population [1]. The neurodegeneration mechanisms have been associated to a complex set of events comprising inflammation, oxidative stress, caused by an overproduction of reactive species (RS), depletion of endogenous antioxidants, protein dysfunction and aggregation, among others, that at the end lead to the demise of neurons [2]. Oxidative stress induced by imbalanced redox states, involving either excessive generation of RS or dysfunction of the antioxidant system, and the higher levels of iron in the brain seems to have a crucial role in NDs progression. So, antioxidant therapy emerged as a useful approach to modulate oxidative stress events [2]. However, despite the promising results obtained in in vitro cell-free and cell-based assays, the pharmacokinetics/pharmacodynamics properties of the majority of antioxidants preclude their advance in pre- and clinical trials [2].

PEGylated platforms engineered to specifically target desired organs, cells or tissues and deliver therapeutic agents across blood-brain barrier has aroused the interest of both academy and industry as a solution for the treatment of NDs [3]. In addition, PEGylation technology has been associated with the improvement of drug solubility and half-life circulation by protecting bioactive moieties against in vivo biological inactivation as well with the decrease of cytotoxicity [4]. In this work, PEGylation was used to ameliorate the bioavailability of two different antioxidant systems based on hydroxycinnamic acids (caffeic (CAF) and ferulic (FER) acids) and the cytotoxicity of a mitochondriotropic antioxidant (AntiOxCIN6) [5-6].

This project was supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, NORTE-01-0145-FEDER-000028, POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-016659 and PTDC/DTP-FTO/2433/2014). C. Fernandes, S. Benfeito, M. Pinto, J. Teixeira and R. Amorim grants were also supported by FCT and FEDER/COMPETE and NORTE 2020 funds.

[1] Mayeux R., Ann. Rev. Neurosci. 2003, 26 (1), 81-104.

[2] Fernandes, C.; Oliveira, C.; Benfeito, S.; Soares, P.; Garrido, J.; Borges, F., Curr. Med. Chem. 2014, 21 (38), 4311-27.

[3] Fernandes, C.; Martins, C.; Fonseca, A.; Nunes, R.; Matos, M.J.; Silva, R.; Garrido, J.; Sarmento, B.; Remião, F.; Otero-Espinar, F.; Uriarte, E.; Borges, F., ACS Appl Mater Interfaces 2018, 10 (46), 39557–39569.

[4] Veronese, F.M.; Pasut, G., Drug Discovery Today 2005, 10 (21), 1451-1458.

[5] Fernandes, C.; Pinto M.; Martins, C.; Gomes, M.J.; Sarmento, B.; Oliveira, P.J.; Remião, F.; Borges, F., Bioconjugate

Chem. 2018, 29 (5), 1677-1689.

[6] Fernandes C, Benfeito, S., Amorim, R., Teixeira, J.; Oliveira, P.J.; Remião, F.; Borges, F., Bioconjugate Chem. 2018,

29 (8), 2723-2733.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

17


Identification of new 4-fluorobenzyl-analogs as tyrosinase inhibitors via computational studies, synthesis and biological evaluation

Laura Ielo,a,b Batel Deri,c Maria Paola Germanò,a Rosaria Gitto,a Serena Vittorio,a Antonio Rapisarda,a Yael Pazy,c Sonia Floris,d Ayelet Fishman,c Antonella Fais,d and Laura De Lucaa

aDept of Chemical, Biological, Pharmaceutical and Environmental Sciences, University of Messina, Viale Palatucci, I-

98168 Messina, Italy

bDept of Pharmaceutical Chemistry, University of Vienna, Althanstraße 14, 1090, Vienna, Austria

cDept of Biotechnology and Food Engineering, Technion-Israel Institute of Technology, 3200003, Haifa, Israel

dDept of Life and Environment Sciences, University of Cagliari, I-09042 Monserrato, Cagliari, Italy


Tyrosinases (Tys, EC 1.14.18.1) are metalloenzymes present in all life domains and involved in the mammal biosynthesis of melanin. Since the over production of melanin can cause serious skin diseases the development of Ty Inhibitors (TyIs) gained high interest in the therapy. Searching for new TyIs from synthetic source, a combination of docking studies and crystal structures furnished suggestion for the synthesis of a large series of small molecules bearing a 4-(4-fluorobenzyl) moiety as key functionality to optimize the ligand-enzyme interaction. As result we identified several derivatives possessing higher efficacy than the reference kojic acid (IC50 = 17.76 µM) as inhibitor of mushroom Ty (TyM) [1,2]. The crystal structures of the most promising compounds in

complex with bacterial Ty (TyBm) were solved confirming the binding poses suggested by in silico studies: the 4’-fluorobenzyl moiety results located between two Cu ions and the aromatic ring appears stabilized through stacking interactions within catalytic pocket. These data were in good agreement with the kinetic analysis demonstrated a competitive mechanism of Ty inhibition. Biological assays showed that the best active inhibitors were able to display antimelanogenic effects without cytotoxicity [3].

[1] Ferro, S.; De Luca, L.; Germanó, M.P.; Buemi, M.R.; Ielo, L.; Certo, G.; Kanteev, M.; Fishman, A.; Rapisarda, A.; Gitto, R., Eur J Med Chem 2017, 125, 992-1001.

[2] Ferro, S.; Deri, B.; Germanó, M.P.; Gitto, R.; Ielo, L.; Buemi, M.R.; Certo, G.; Vittorio, S.; Rapisarda, A.; Pazy, Y.; Fishman, A.; De Luca, L., J Med Chem 2018, 61, 3908-3917.

[3] Ielo, L.; Deri, B.; Germanò, M.P.; Vittorio, S.; Mirabile, S.; Gitto, R.; Rapisarda, A.; Ronsisvalle, S.; Floris, S.; Pazye, Y.; Fais, A.; Fishman, A.; De Luca, L., submitted for publication.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

18


Molecular modeling of epitopes recognized by neoplastic B-cells in Chronic Lymphocytic Leukemia

Antonio Lupia,a,b Selena Mimmi,c Enrico Iaccino,c Federica Moraca,a,d Domenico Maisano,a,c Eleonora Vecchio,c Carmine Talarico,a Giuseppe Fiume,c Francesco Ortuso,a,b Giuseppe Scala,c Stefano Alcaro,a,b and

Ileana Quinto, c a Dipartimento di Scienze della Salute, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy


c Department of Experimental and Clinical Medicine, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy

d Department of Pharmacy, University Federico II of Naples, Via D. Montesano 49, 80131-Napoli, Italy


Chronic Lymphocytic Leukemia (CLL) is a neoplastic disease of mature B-cells that express a functional Immunoglobulin B-cell receptor (Ig-BCR) on cell surface [1]. The Ig-BCR includes the binding site (idiotype) for the epitope of cognate antigen, which results from stochastic and productive Ig variable genes rearrangement, and possible somatic hypermutations. Individual B-cells clones differ from one another because of the diverse amino acid sequences within the idiotype of the expressed Ig-BCR. The screening of phage-displayed peptide libraries (RPLs) is a powerful tool for the selection of peptide binders of the idiotypic region of IgBCRs, which are called Id-peptides (Figure 1) [2]. By analysing the antigenic reactivity of the neoplastic populations of six CLL patients, we selected a pool of eleven Id-peptides. Four of them were classified as cross-reactive (CR)” Id-peptides, due to their same spectrum of binding reactivity. Otherwise, the other Id-peptides were classified as “NO-cross-reactive (NCR)” Id-peptides. Thus, by using the pharmacophore approach and the LB-3D-QSAR methodology, we investigated the common chemical features of the CR Id-peptides that sharing epitopic profile of CLL sub-populations and we designed new cyclic peptides structures useful for functional assays on primary CLL cells. Our findings underline the value of pharmacophore approach as tool for the chemical features characterization of IgBCR epitopic reactivity in the context of B cell neoplastic aberrations.

Figure 1: Schematic representation of Id-peptides binding the BCR on B-cell surface.

[1] Zenz T., Mertens D., Kuppers R., Dohner H., Stilgenbauer S. Nat Rev Cancer. 2010; 10: 37–50

[2] Mimmi, S., Maisano, D., Quinto, I. & Iaccino, E. Trends Pharmacol Sci. 2018; 40:87-91.

[3] Mimmi S., Vecchio E., Iaccino E., Rossi M., Lupia A., Albano F., Chiurazzi F., Fiume G., Pisano A., Ceglia S., Pontoriero M., Golino G., Tassone P., Quinto I., Scala G., Palmieri C. Leukemia. 2016; 30: 2419-2422.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

19


Design and development of multi-target agents for neurodegenerative diseases Sofia Benfeito,a Fernando Cagide,a Catarina Oliveira,a Carlos Fernandes,a José Teixeira,a,b Ricardo Amorim,a,b

R. Silva,c Fernando Remião,c Eugenio Uriarte,d Paulo J. Oliveira,b Fernanda Borgesa

aCIQUP, Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal

bCNC – Center for Neurosciences and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede,

Portugal cUCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of

Porto, Porto, Portugal dApplied Chemical Science Institute, Autonomous University of Chile, Santiago de Chile, Chile


Neurodegenerative diseases are progressive neurological disorders associated with central nervous system (CNS) dysfunction. In Alzheimer's disease (AD), the most prevalent disorder, the pathogenesis has been linked to the oxidative stress and impaired of cholinergic transmission, resulting in memory loss and cognitive decline. Despite the existence of some approved cholinergic drugs towards AD, none of them demonstrated effectiveness to modify disease progression. Accordingly, the development of new chemical entities acting in more than one target is attracting progressively more attention. In this way, the focus of the current work was the design and synthesis of new multi-target-directed antioxidants (MTDAs) based on dietary scaffolds, capable to prevent oxidative cascade events and improve cholinergic neurotransmission [1,2]. To establish robust structure-property-activity relationships several chemical modifications were performed on the aromatic pattern of naturally occurring hydroxycinnamic and hydroxybenzoic acids, on the length of spacer between carboxamide and aromatic ring and on the linker between carboxamide and triphenylphosphonium cation (TPP+). The assessment of in vitro antioxidant activity in cell-free and cell-based systems (SH-SY5Y and HepG2), the cholinergic inhibitory activity towards eqAChE and eqBChE, as well as in vitro blood-brain barrier permeability using hCMEC/D3 cells have been performed. The results obtained so far will be presented in this communication. This project was supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, NORTE-01-0145-FEDER-000028, POCI-01-0145-FEDER-007440, POCI-01-0145-FEDER-016659 and PTDC/DTP-FTO/2433/2014). S. Benfeito, F. Cagide, C. Oliveira, C. Fernandes, J. Teixeira and R. Amorim grants were also supported by FCT and FEDER/COMPETE and NORTE 2020 funds.

[1] Teixeira J., Cagide F., Benfeito, et al., Journal of Medicinal Chemistry, 2017, 60, 7084-7098.

[2] Benfeito S., Oliveira C., Fernandes C., et al., European Journal of Medicinal Chemistry, 2019, 167, 525-545.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

20


Pyrido[2,3-d]pyrimidine-7(8H)-ones: synthesis and biomedical applications

José I. Borrell

Grup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, 08017 Barcelona,

Catalunya (Spain)


Pyrido[2,3-d]pyrimidines (1) are a type of privileged heterocyclic scaffolds [1] capable of providing ligands for several receptors in the body [2].

Among such structures, our group and others have been particularly interested in pyrido[2,3-d]pyrimidine-

7(8H)-ones (2) due to the similitude with nitrogen bases present in DNA and RNA. A search carried out in SciFinder reveals that there are more than 21,700 structures described which correspond to 2761 references (1329 of them being patents). Furthermore, a plot of the number of references containing compounds of general structure 2 versus the year of publication (Figure 1) clearly shows how they have rapidly increased in the past 20 years.

The present communication reviews the synthetic methods used for the synthesis of pyrido[2,3-d]pyrimidine-7(8H)-ones (2), both starting from a preformed pyrimidine ring or a pyridine ring, and the biomedical applications of such compounds.

Figure 1: Pyrido[2,3-d]pyrimidines (1) and pyrido[2,3-d]pyrimidine-7(8H)-ones (2).

[1] (a) Evans B.E.; Rittle K.E.; Bock M.G.; DiPardo R.M.; Freidinger R.M.; Whitter W.L.; Lundell G.F.; Veber D.F.; Anderson P.S.; Chang R.S.; et al., Journal of Medicinal Chemistry 1988, 31 (12), 2235-2246. (b) Welsch M.E.; Snyder S.A.; Stockwell B.R., Current Opinion in Chemical Biology 2010, 14, 347–361.

[2] Selvam, T.P.; James, C.R.; Dniandev, P.V.; Valzita, S.K., Research in Pharmacy 2012, 2, 1–9.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

21


Design and Development of New Chemical Concepts via Controlled Generation of

Unstable Carbenoids Species

Vittorio Pace

Department of Pharmaceutical Chemistry, University of Vienna, Althanstrasse 14, 1090 Vienna (Austria). Email: [email protected]; web: drugsynthesis.univie.ac.at

The transfer of a reactive nucleophilic CH2X unit into a preformed bond enables the introduction of the fragment featuring the exact and desired degree of functionalization through a single synthetic operation.1 The instability of metallated α-organometallic species often poses serious questions on the practicability of using this conceptually intuitive and simple approach for forming C-C or C-heteroatom bonds. The deep understanding of processes regulating the formation of these nucleophiles is a precious source of inspiration not only for successfully applying theoretically feasible transformations (i.e. determining how to employ a given reagent), but also for designing new reactions which ultimately lead to introduce molecular complexity via short experimental sequences as flash accesses to quaternary aldehydes, telescoped homologations and nucleophilic fluoromethylations, inter alia.2

Three Concepts MergedHomologation - Isomerization - Electrophilic Trapping

R

O

R2

R1

R R2

R1O

R R2

R1 O

R3

LiCH2Xhomologation

Meinwaldrearrangement

(R3X)

electrophilic trapping

one-step

NR

F3C

Cl (2.8 equiv)

F3C Cl

NR

NR

X

F3CC1homologation

Quaternary CF3-bearing carbon assembled during the homologation

(1.2 equiv)

C1-C1homologation

Li X

Li XLi X

Two possible different

New motifs Modular approach Full chemocontrol X = Cl, F

(1) Castoldi, L.; Monticelli, S.; Senatore, R.; Ielo, L.; Pace, V. Chem. Commun. 2018, 54, 6692-6704.

(2) (a) Pace, V.; Castoldi, L.; Mazzeo, E.; Rui, M.; Langer, T.; Holzer, W. Angew. Chem. Int. Ed. 2017, 56, 12677-12682.

(b) Parisi, G.; Colella, M.; Monticelli, S.; Romanazzi, G.; Holzer, W.; Langer, T.; Degennaro, L.; Pace, V.; Luisi, R. J. Am. Chem. Soc. 2017, 139, 13648-13651. (c) Castoldi, L.; Pace, V. Nature Chem. 2018, 10, 1081-1082. (d) Ielo, L.; Touqeer, S.; Roller, A.; Langer, T.; Holzer, W.; Pace, V. Angew. Chem. Int. Ed. 2019, 58, 2479-2484.. (e) Monticelli, S.; Colella, M.; Pillari, V.; Tota, A.; Langer, T.; Holzer, W.; Degennaro, L.; Luisi, R.; Pace, V. Org. Lett. 2019, 21, 584-588.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

22


Lessons from black pepper: moving from one to multitarget-directed ligands by diversity-oriented synthesis

Daniel Chavarria,a,b Carlos Fernandes,a Fernando Remião,c Paulo Jorge Oliveirab and Fernanda Borgesa

a CIQUP/Depart. of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal.

b CNC – Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech Building, Biocant Park,

Cantanhede, Portugal. c UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of

Porto, Porto, Portugal.


Parkinson’s disease (PD) is a multifactorial age-related disorder clinically characterized by distinct motor deficits, such as bradykinesia, rigidity and resting tremor [1]. The Parkinsonian motor symptoms have been associated to the selective and progressive loss of dopaminergic neurons in Substantia Nigra, resulting in nigrostriatal dopamine deficiency [2]. Dopamine is deaminated into the corresponding aldehyde and hydrogen peroxide by two isoforms of monoamine oxidase (MAO), MAO-A and MAO-B [3], although it is mainly metabolized by MAO-B in Substantia Nigra [4]. The use of MAO-B inhibitors is, therefore, a strategy to block the dopamine degradation in the nigrostriatal pathway [2] and to prevent the formation of potentially toxic products [3]. Oxidative stress also plays a pivotal role on the cascade leading to the degeneration of dopaminergic neurons in PD [5]. In this context, the use of antioxidants can be an effective therapeutic approach to prevent or treat the oxidative damage events.

As part of our drug discovery programs, we developed a small piperine-based library aimed to find out new molecules able to act as MAO-B inhibitors and as antioxidants. Twenty-five piperine derivatives were successfully obtained. The hMAO inhibitory activities and the hMAO-B inhibition mechanism were evaluated by spectrophotometry. The antioxidant properties were studied using fluorometric and voltammetric assays. The cytotoxicity was assessed in differentiated SH-SY5Y cells. The results obtained so far will be presented in this communication.

This project was supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, POCI-01-0145-FEDER-006980, and NORTE-01-0145-FEDER-000028). D. Chavarria (SFRH/BD/108119/2015) grant was also supported by FCT and FEDER/COMPETE funds.

[1] D. Charvin, R. Medori, R. A. Hauser, and O. Rascol, Nature reviews. Drug discovery 2018, 17 (11), 804-822.

[2] M. H. Nam, M. Park, H. Park, Y. Kim, S. Yoon, V.S. Sawant, J.W. Choi, J.H. Park, K.D. Park, S.J. Min, C.J. Lee, H. Choo, ACS Chemical Neuroscience 2017, 8 (7), 1519-1529.

[3] J. P. M. Finberg, Journal of Neural Transmission (Vienna, Austria: 1996) 2018, 1-16.

[4] N.T. Tzvetkov, H. G. Stammler, B. Neumann, S. Hristova, L. Antonov, and M. Gastreich, European Journal of Medicinal Chemistry 2017, 127, 470-492.

[5] P. Jenner, Annals of Neurology 2003, 53 Suppl 3, S26-S36.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

23


Position-Selective Synthesis and Biological Evaluation of Four Isomeric A-Ring Amino Derivatives of the Alkaloid Luotonin A

Amra Ibric,a Stefan Eckerstorfer,a Martin Eder,a Ivan Louko,a Leopold Tunjic,a Petra Heffeter,b Hemma Henrike Schueffl,b Brigitte Marianb and Norbert Haidera

a Department of Pharmaceutical Chemistry, University of Vienna,

Althanstraße 14, A-1090 Vienna, Austria b Institute of Cancer Research and Comprehensive Cancer Center, Medical University of Vienna,

Borschkegasse 8a, A-1090 Vienna, Austria


In the course of a project aiming at the discovery of new and potentially useful Topoisomerase I (Topo I) inhibitors, using Luotonin A as the lead structure, we synthesized several new members of this compound family that demonstrate additional biological activity. We prepared a series of all four possible A-ring amino derivatives of the natural product Luotonin A, following two orthogonal synthetic routes that are suitable for the specific placement of substituents [1-4]. The target compounds were obtained in good yields and they were subjected to a detailed in vitro evaluation. Three of four examined compounds were found to be clearly superior to Luotonin A, inhibiting the Topo I enzyme in human tumor cell lines. Especially the 4-amino compound showed an interesting profile of cytotoxic activity, being at the same time the most effective representative of this series. Besides topoisomerase I inhibition (that was confirmed in a DNA relaxation assay), a significant G2/M arrest was observed under exposure of malignant cells to this compound, followed by significant morphological aberrations of treated cells. These observations suggest that some atypical or additional mechanism could be responsible for the cytotoxic activity of this compound.

1

2

3

4 5

6

7 8

9

10

11

12

1314

A B C

D

E

NH2

N

N

N

O

[1] Liang, J.L.; Cha, H.C.; Jahng, Y., Molecules, 2011, 16, 4861-4883.

[2] Atia, M.; Bogdan, D.; Brugger, M.; Haider, N.; Matyus, P., Tetrahedron, 2017, 73, 3231-3239.

[3] Haider, N.; Nuss, S.; Molecules, 2012, 17, 11363-11378.

[4] Haider, N.; Meng, G.; Roger, S.; Wank, S., Tetrahedron, 2013, 69, 7066-7072.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

24

• Mitochondrial Destruction

• CDC25 Inhibition

• Redox Toxicity

Cancer Cell Death

Multitargeted


Synthesis of Cytotoxic Isoquinolinequinone N-oxides as Multitargeted Agents

Ryan D. Kruschel,a and Florence O. McCarthya aSchool of Chemistry, Analytical and Biological Chemistry Research Facility, University College Cork, Cork, Ireland.


The isoquinolinequinone (IQQ) pharmacophore is a privileged framework in known cytotoxic natural product metabolites, caulibugulones and mansouramycins both isolated from marine sponges [1]. Both series exhibit cytotoxicity in the sub-micromolar range across multiple cancer cell lines including renal, breast and ovarian. A multitargeted approach is often adopted to explain the IQQ’s potent cytotoxicity. This includes mitochondrial destruction through redox cycling and enzyme inhibition through electrophilic addition to critical amino acids in vivo for example in Cdc25 isoforms, whose function is crucial in normal cell cycle regulation [2,3]. We report on the discovery of a potent novel anticancer N-oxide derived framework (Figure 1). A library of novel IQQ’s were synthesised exhibiting nM cytotoxic activity against breast, melanoma and ovarian cancer cell lines. A lead compound has been identified to conduct further mechanistic studies in view of progression towards clinical development.

Figure 1: Novel IQQ framework derived from marine metabolites families, Mansouramycin and Caulbugulone

[1] Milanowski, J.D. et al., Journal of Natural Products, 2004, 67, 70-73

[2] Hawas W.U. et al, Journal of Natural Products, 2009, 72, 2120-2124

[3] Kuang S. et al, Oncotarget, 2017, 61, 104057-104071

[4] Brisson M. et al., Molecular Pharmacology, 2007, 71, 184-192

BOOK of ABSTRACTS

MedChem2019




-15th

2019

25


Synergistic inhibition of the Hedgehog pathway by newly designed Smo and Gli antagonists bearing the isoflavone scaffold

Silvia Balducci,a Simone Berardozzi,a,b Flavia Bernardi,c Paola Infante,b Cinzia Ingallina,a Sara Toscano,a Elisa De Paolis,a,b Romina Alfonsi,c Miriam Caimano,c Bruno Botta,a Mattia Mori,b Lucia Di Marcotullio,c,d and

Francesca Ghirga,b a Department of Chemistry and Technology of Drugs, Sapienza University, Rome

bCenter for Life Nano Science@Sapienza, Italian Institute of Technology, Rome, Italy

cDepartment of Molecular Medicine, Sapienza University, Rome, Italy

dIstituto Pasteur-Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161 Rome, Italy


Hedgehog (Hh) signaling has emerged in recent years as a druggable target for anticancer therapy [1]. Its aberrant activation, occurring either by ligand-dependent or -independent mechanisms, has been observed in many tumors. Thus, small molecules able to block the pathway at the upstream receptor Smoothened (Smo) or the downstream effector Gli1 have emerged as valuable anticancer agents [2]. We previously identified Glabrescione B (GlaB), an isoflavone naturally found in the seeds of Derris glabrescens (Leguminosae), as a novel small molecule that proved to be able to bind Gli1ZF and interfere with its interaction with DNA [3].We provided the total synthesis of GlaB which foresees a mild and cost effective three-step protocol based on the deoxybenzoin [4].This synthetic strategy allowed us the design and preparation of a small-size focused library of isoflavones bearing different substitutions at the ring B to elucidate the structure-activity relationships and the molecular mechanism behind the Hh signaling modulation. Target preference has been achieved by the introduction of specific bulky substitutions at meta position (targeting GLI1) or para position (targeting SMO) of the isoflavone’s ring B [4]. Interestingly, the combined administration of two different isoflavones behaving as SMO and GLI1 antagonists, respectively, in primary MB cells has shown synergistic Hh inhibition at doses that are around 20-fold lower than individual compound doses, thus leading the way to further and innovative combination therapy for the treatment of Hh-dipendent tumors.

[1] Ruiz Altaba A.; Sanchez, P.; Dahmane, N., Nature Review Cancer 2002, 2(5), 361-372.

[2]. Ghirga F.; Mori M.; Infante P., Bioorganic & Medicinal Chemistry Letters 2018, 3131-3140.

[3]. Infante P.; Mori M.; Alfonsi R.; Ghirga F.; Aiello F.; Toscano S.; Ingallina C.; Siler M.; Cucchi D.; Po A.; Miele E.; D'Amico D.; Canettieri G.; De Smaele E.; Ferretti E.; Screpanti I.; Uccello Barretta G.; Botta M., Botta B.; Gulino A., Di Marcotullio L., The EMBO Journal 2015, 34, 200-217.

[4]. Berardozzi S.; Bernardi F.; Infante P.; Ingallina C.; Toscano S., De Paolis E.; Alfonsi R.; Caimano M.; Botta B.; Mori M.; Di Marcotullio L.; Ghirga F., European Journal of Medicinal Chemistry 2018, 156, 554-562.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

26


Multi-target design of arginase inhibitors for Leishmania

Alfonso T. García-Sosa,a a Institute of Chemistry, University of Tartu, Ravila 14a, 50411 Tartu, Estonia


There are no vaccines against human leishmaniasis. Current chemotherapy induces side effects and drug resistance. Thus, the development of new and effective agents is essential. At the same time, multi-target drug design is an evolving paradigm that allows considering several targets simultaneously for better medicinal chemistry outcomes [1]. Novel oxadiazoles and indolizine-containing compounds were screened in silico by long-range interaction filters, ligand-based virtual screening, and molecular docking to parasite arginase, human arginase, and an anti-target battery to tag possible interactions with receptors involved in the metabolism and clearance of many substances [2]. Measurable in vitro anti-leishmanial activity was shown for three compounds. Compound 2 (Figure 1), with an IC50 value of 2.18 µM on Leishmania donovani intramacrophage amastigotes and with the best selectivity index at a level of cytotoxicity similar to that of the reference drug Amphotericin B, is an interesting molecular template for further development of new anti-leishmanial agents [3].

Figure 1: Novel Leishmania donovani amastigote inhibitor.

[1] Alcaro, S.; Bolognesi, M.L.; García-Sosa, A.T.; Rapposelli, S., Front. Chem. 2019, 7, 71.

[2] García-Sosa, A. T.*, Curr. Comp.-Aided Drug Des. 2018, 14( 2), 131-141.

[3] Stevanovic, S.; Sencanski, M.; Danel, M.; Menendez, C.; Belguedj, R.; Bouraiou, A.; Nikolic, K.; Cojean, S.; Loiseau, P.M.; Glisic, S.; Baltas, M.; García-Sosa, A. T.*, Molecules 2019, 24 (7), 1282.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

27


Synthesis and biological evaluation of 1’-N-homoazanucleosides: discovery of a 5’-

methylthioadenosine analogue with antitrypanosomal activity

Jakob Bouton, Serge Van Calenbergh

Laboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium

email : [email protected]

Azanucleosides are a class of nucleoside analogues in which the furanose ring has been replaced by a functionalized iminosugar. The presence of the central nitrogen atom in the sugar mimic allows several of these azanucleosides to act as transition state analogue enzyme inhibitors of nucleoside processing enzymes. This results in a wide spectrum of biological activities, most notably in the area of infectious diseases [1]. The majority of known azanucleosides are either aza-C-nucleosides, or homonucleosides, in which a methylene linker is placed between the sugar mimic and the nucleobase.

Inspired by the intriguing biological activities of known azanucleosides, we became interested in the exploration of 1’-N-homoazanucleosides. A series of new 1’-N-homoazanucleosides was synthesized in a convergent fashion, using a protected iminosugar scaffold that was subsequently functionalized with a number of purine and pyrimidine nucleoside analogues. The adenosine analogue was then further derivatized by introducing thioether substituents on the 5’-position, resembling the structure of 5’-methylthioadenosine (5’-MTA).

The synthesized compounds were broadly evaluated in vitro against a panel of disease-relevant pathogens (including viruses, bacteria, and parasites). The 5’-methylthioadenosine analogue emerged as an interesting hit for Trypanosoma brucei.

HN

HO OH

R

BASE

O O

O

OTBS

O+

H

HN

HO OH

S

N

N

N

N

H2N

T. brucei IC50 = 1.88 µM(20 examples)

[1] Evans, G. B. et al. ACS Infectious Diseases, 2018, 4(2), 107-117.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

28


Halogenated phenothiazines targeting the M. Tuberculosis type II of the NADH

dehydrogenase.

Maria Giulia Nizi,a Serena Massari,a Maria Angela Mazzarella,a Sang Hyun Cho,b Rui Ma,b Baojie Wan,b Scott G. Franzblau,b and Oriana Tabarrinia

a Department of Pharmaceutical Sciences, Università degli Studi di Perugia, Via del Liceo, 1, 06123-Perugia, Italy

b Institute for Tuberculosis Research, College of Pharmacy, MIC 964, Rm. 412, University of Illinois at Chicago, IL,

60612, USA


Respiratory chain is a series of membrane-bound enzymes involved in the generation of ATP in many microorganisms including in Mycobacterium Tuberculosis and that gained attention for their fundamental importance in different phases of M. Tuberculosis life. In particular, one of the most investigated enzyme is the type II of NADH dehydrogenase (NDH-II), of which mammalian cells are lacking. For these reasons, various NDH-II inhibitors have been reported in the literature that confirm its validity as innovative target to obtain an anti-tubercular effect. Among them there are some phenothiazine derivatives, including therapeutic thioridazine and chlorpromazine [1].

Thus, by a repurposing approach, a set of in-house phenothiazines were assayed against M.Tuberculosis. Based on promising results, additional derivatives were designed. In particular, the N-10 position was explored by introducing different alkylamino chains, along with halogen atoms placed in different positions of the core to exploit the ability of halogen bonding to improve the target recognition, an approach that have recently attracted the attention of medicinal chemists [2].

All the new derivatives were assayed for their activity against M.Tuberculosis H37Rv strain in parallel with the cytotoxicity. The best compounds were subjected to an in-depth evaluation to assess: the NDH-II inhibition, the bactericidal effect, and the synergistic effect in checkerboard assay combining them with known anti-tubercular drugs. Finally, the most promising compounds are under evaluation against a panel of dopamine/serotonin receptors in order to study their safety profile.

The design, synthesis and the biological evaluation will be reported.

[1] Yano, T.; Weinstein, E.; Teh, J.; Rubin, H. Journal of biological chemistry, 2006, 281 (17), 11456-63.

[2] Kolar, MH.; Tabarrini, O. Journal of Medicinal Chemistry, 2017, 60 (21), 8681-8690.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

29


A target for macrocyclic antifungals: the needle in the haystack Diego Fiorucci,a Giorgio Maccari,a Francesco Orofino,a Maurizio Bottaa,b,c

a Dept. of Biotechnology, Chemistry and Pharmacy, University of Siena, via A. Moro, 2, 53100 Siena, Italy b

Sbarro Institute for Cancer Research and Molecular Medicine, Temple University, BioLife Science Bldg., Suite 333, 1900 N

12th Street, Philadelphia, PA 19122, USA cLead Discovery Siena s.r.l, Via Vittorio Alfieri 31, I-53019 Castelnuovo Berardenga (SI),


Systemic fungal infections, nowadays, are taking on a primary role in cases of viral infections such as HIV, in transplanted or chemio/radiotherapy patients, or in general, in situations that the immune system may result unable to manage. The onset of resistance, along with the fact that very few new classes of antifungals have been discovered, makes the research in this field of great importance and interest worldwide. In the last decade, our group explored the potential of new non-azole macrocyclic compounds, endowed with interesting antifungal activity. [1]

The efforts have been focused on the identification of the mode of action of the hit compound, analyzing the gene up-regulation in strains exposed to the molecule. Interesting information have been collected, in fact, it has been noticed that Fluconazole resistant strains are more susceptible to our hit compound compared to the azole sensible ones. A correlation between the overexpression of the ABC transporter CDR1, 2, and 6 with the activity of our compound has been demonstrated. [2] In parallel a computational approach has been applied. To identify a putative target, it has been set up a computational target fishing procedure that highlighted the Chitinase protein as potential target of this series of compounds. [3] Chitinases resulted to be a hot topic recently, because of their involvement in many parasites life cycles and in human inflammatory pathologies, hence we rationally designed and investigated macrocyclic derivatives as Chitinase inhibitors, exploring the possibilities of this scaffold. Preliminary in vitro assays against T. viride Chitinase have been performed, leading to the identification of a promising HIT compounds to be further improved, with a 50-fold improvement in terms of Ki if compared to the previously tested compounds.

[1] Sanguinetti, M.; Sanfilippo, S.; Castagnolo, D.; Sanglard, D.; Posteraro, B.; Donzellini, G.; Botta, M. Novel Macrocyclic Amidinoureas: Potent Non-Azole Antifungals Active Against Wild-Type and Resistant Candida Species. ACS Med. Chem. Lett. 2013, 4 (9), 852–857.

[2] Deodato, D.; Maccari, G.; De Luca, F.; Sanfilippo, S.; Casian, A.; Martini, R.; D'Arezzo, S.; Bonchi, C.; Bugli, F.; Posteraro, B.; Vandeputte, P.; Sanglard, D.; Docquier, J. D.; Sanguinetti, M.; Visca, P.; Botta, M. Biological Characterization and in Vivo Assessment of the Activity of a New Synthetic Macrocyclic Antifungal Compound. J. Med. Chem. 2016, 59 (8), 3854–3866.

[3] Maccari, G.; Deodato, D.; Fiorucci, D.; Orofino, F.; Truglio, G. I.; Pasero, C.; Martini, R.; De Luca, F.; Docquier, J. D.; Botta, M. Design and Synthesis of a Novel Inhibitor of T. Viride Chitinase Through an in Silico Target Fishing Protocol. Bioorganic & Medicinal Chemistry Letters 2017, 27 (15), 3332–3336.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

30


Design and synthesis of Mycobacterium tuberculosis

thymidylate kinase (MtTMPK) inhibitors

Yanlin Jian,a Martijn D.P. Risseeuw,a Helena I. Boshoff,b Hélène Munier-Lehmannc and Serge Van Calenbergha

a Laboratory for Medicinal Chemistry, Faculty of Pharmaceutical Sciences, Ghent University. Ottergemsesteenweg 460,

B-9000, Ghent, Belgium. b Tuberculosis Research Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and

Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA. c Institut Pasteur, Unit of Chemistry and Biocatalysis, Department of Structural Biology and Chemistry, 28 Rue du Dr.

Roux, 75724 Paris Cedex 15, France


Thymidylate kinase (TMPK) catalyzes the phosphorylation of thymidine 5’-monophosphate to the corresponding diphosphate and is indispensable for growth and survival of Mycobacterium tuberculosis. This makes it a promising target in the development for new drugs for the treatment of TB [1]. Starting from the earlier identified thymine-based hit 1[2], efforts were made to develop more potent mtbTMPK inhibitors that demonstrate antimycobacterial activity. Here, we will present our efforts towards this goal.

N

HNO O

NN

N

HNO O

N

OH

OHO

O

N

O

12 nM>54 mg/ml

Ki:MIC H37Rv: KO-Mmr:

2

N

HNO O

NN

3

2500 nM4.7 mg/ml

1 N

800 nM>250 mg/ml<2 mg/ml

Ki:MIC H37Rv:

Ki:MIC H37Rv:

[1] Van Calenbergh, S.; Pochet, S; and Munier-Lehmann, H. Drug design and identification of potent leads against mycobacterium tuberculosis thymidine monophosphate kinase. Curr. Top. Med. Chem. 2012, 12, 694-705.

[2] Song. L.; Merceron, R.; Gracia, B.; Quintana, A.L.; Risseeuw, M.D.P.; Hulpia, F.; Cos, P.; Aínsa, J.A.; Munier-Lehmann, H.; Savvides, S.N. and Van Calenbergh, S. Structure Guided Lead Generation toward Nonchiral M. tuberculosis Thymidylate Kinase Inhibitors. J. Med. Chem. 2018, 61, 2753−2775.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

31

MuTaLig COST Action Short Communications

BOOK of ABSTRACTS

MedChem2019




-15th

2019

32

MuTaLig COST Action Short Communication 1 (CA-SC_1)

Maintaining the neurotransmitter pool in degenerating brain: parameters for propargylamine inhibition of monoamine oxidase

Rona R. Ramsay,a and Stefanie Hagenowb a Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St

Andrews KY16 9ST, United Kingdom b Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, , Universitaetsstr. 1,

40225 Duesseldorf, Germany.


Phenelzine, tranylcypromine, pargyline and selegiline are drugs that inactivate monoamine oxidases to slow neurotransmitter metabolism in depression and neurodegenerative diseases. The drugs are oxidized by monoamine oxidase (MAO) to a reactive product that forms a covalent adduct with the flavin cofactor in MAO. The reactive fragments, in particular the propargylamine moiety of pargyline and selegiline, are of interest in the design of multi-target compounds to combat neurodegeneration, so we have determined the kinetic parameters (Fig. 1) that define the interaction of these established drugs with human MAO A and MAO B expressed in insect cells, the form now used to assess novel compounds. The Ki values for binding to MAO A show that selectivity is determined by the initial binding. The kinact values for active compounds vary in a narrow range of 0.1 to 0.7 min-1. The rate of MAO A reduction and the rate of adduct formation are equal for pargyline and for clorgyline, compounds with partition ratios close to unity, but reduction is faster than adduct formation for the multitarget compound ASS234 [1] allowing some product to dissociate from the enzyme. Computational modeling has provided information on the key interactions for selectivity and efficient oxidation, and for the interactions of the products with reduced MAO that define the partition between adduct formation and product release.

Figure 1: Optimizing adduct formation for inactivation of monoamine oxidase by propargylamines.

[1] Albreht, A.; Vovk, I.; Mavri, J., Marco-Contelles, J.; Ramsay, R.R. 2018. Front. Chem. 6:169. doi: 10.3389/fchem.2018.00169

BOOK of ABSTRACTS

MedChem2019




-15th

2019

33


Expanding the coumarin toolbox directed at CNS multitargeting agents Leonardo Pisani,a Marco Catto,a Mariagrazia Rullo,a Modesto De Candia,a and Cosimo D. Altomarea

a Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”,

via Orabona 4, 70125-Bari, Italy


Despite huge efforts, no curative therapies for Alzheimer’s disease (AD) are available to clinicians that can only attenuate symptoms in earlier stages by means of palliative drugs. Our contribute to the multitargeting drugs’ field followed in the footsteps signed by Ladostigil [1], a dual irreversible inhibitor blocking both the activity of acetylcholinesterase (AChE) and monoamine oxidases (MAOs), thus counteracting cholinergic deficit and oxidative stress conditions. Structure-based, ligand-based and “design-in” approaches were applied to decorate the coumarin motif with the aim of identifying novel dual AChE-MAO B inhibitors with different bioactivity profiles [2] and triple-acting compounds (AChE-MAO B inhibitors acting as NO donors) [3]. Throughout a property-based hit optimization we succeeded in identifying different hit compounds endowed with outstanding in vitro inhibitory activity and selectivity towards eeAChE (vs. hsBChE) and hMAO B (vs. hMAO A), along with promising drug-like features as potential anti-Alzheimer tools. Preliminarily, water solubility and chemical (and/or serum) stability were evaluated in vitro along with cytotoxicity, blood-brain barrier permeation, and neuroprotection against pro-oxidative insults in cell-based models.

Figure 1: Coumarin-based multitarget hits.

[1] Sterling, J.; Herzig, Y.; Goren, T.; Finkelstein, N.; Lerner, D.; et al., J. Med. Chem. 2002, 45, 5260−5279.

[2] Pisani, L.; Farina, R.; Catto, M.; Iacobazzi, R.M.; et al., J. Med. Chem. 2016, 59, 6791−6806.

[3] Pisani, L.; Iacobazzi, R.M.; Catto, M.; Rullo, M.; et al., Eur. J. Med. Chem. 2019, 161, 292-309.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

34


4-(3-Nitrophenyl)thiazol-2-ylhydrazone derivatives as selective hMAO-B inhibitors: synthesis, biological activity and computational analysis

Giulia Rotondi,*a Paolo Guglielmi,a Simone Carradori,b Jacobus P. Petzer,c Francesco Ortuso,d and Daniela Seccia

a Dipartimento di Chimica e Tecnologie del Farmaco, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome Italy

b Department of Pharmacy, “G. D’Annunzio” University of Chieti Pescara, Via dei Vestini 31, 66100 Chieti, Italy

c Pharmaceutical Chemistry and Centre of Excellence for Pharmaceutical Sciences, North-West University,

Potchefstroom 2520, South Africa d

Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Campus “S. Venuta”, Viale Europa, 88100 Catanzaro, Italy


With the aim to widen our knowledge on the 4-(3-nitrophenyl)thiazol-2-ylhydrazone scaffold [1], we designed, synthesized and tested compounds 1-37, bearing at N1 new X and Y substituents, as hMAO-A and hMAO-B inhibitors (Figure 1).

N

HN

S

N NO2 (NH2 for 37)

X

Y

X H, CH3, CH2CH3 Y Heterocycles, phenyl ring, substituted phenyl ring Figure 1: Structure of derivatives 1-37.

All the tested compounds were found to inhibit selectively hMAO-B with a reversible and competitive mechanism of inhibition. Most of them were active in the nanomolar range. The loss of hMAO-B inhibitory activity observed for derivative 37 confirmed the importance of the nitro group at the meta position of this nucleus. Moreover, the molecular modelling studies and the theoretical properties provided insights into the multiple interactions and the pharmacokinetic parameters of the reported compounds [2].

[1] Carradori, S.; Ortuso, F.; Petzer, A.; Bagetta, D.; De Monte, C.; Secci, D.; De Vita, D.; Guglielmi, P.; Zengin, G.; Aktumsek, A.; Alcaro, S.; Petzer, J. P., European Journal of Medicinal Chemistry 2018, 143, 1543-1552.

[2] Secci, D.; Carradori, S.; Petzer, A.; Guglielmi, P.; D’Ascenzio, M.; Chimenti, P.; Bagetta, D.; Alcaro, S.; Zengin, G.; Petzer, J. P.; Ortuso, F., Journal of Enzyme Inhibition and Medicinal Chemistry 2019, 34 (1), 597-612.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

35


Probing fluorine-effects in multitarget anti-Alzheimer agents

Mariagrazia Rullo,a Leonardo Pisani,a Marco Catto,a Nicola Giacchè,b and Cosimo D. Altomarea

a Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, via Orabona 4, 70125, Bari, Italy

b TES Pharma s.r.l., Corso Vannucci 47, 06121, Perugia, Italy


Alzheimer’s disease (AD) is a neurodegenerative process, ultimately fatal, representing the most common cause of dementia. Given the multifactorial nature, the research recently shifted to the more promising multitarget strategy, which aims at developing rationally designed Multi-Target-Directed Ligands (MTDLs) [1], that challenge the synergy of modulating two (or more) relevant AD targets through a unique chemical entity. Our efforts have long been devoted to discovering dual coumarin-based selective inhibitors of monoamine oxidase B (MAO B) and acetylcholinesterase (AChE), both playing a key role in AD, by means of structure-based hybridization strategies [2] and “design-in” approaches [3], leading to outstanding in vitro activity and selectivity. More recently, we were intrigued about studying the effect of fluorine atom(s) on both in vitro potency and drug-like features of our dual hits. The introduction of a m-fluoro substituent on

the phenyl ring led to dual selective inhibitors showing submicromolar IC50 toward AChE (0.14 µM ≤ IC50 ≤

0.65 µM) and MAO B inhibitory potency in the low nanomolar range (0.010 µM ≤ IC50 ≤ 0.14 µM). Moreover, the bioisosteric replacement of primary alcohols with gem-difluoromethyl groups [4] returned equipotent, yet highly active, dual AChE-MAO B inhibitors.

Figure 1: Fluorine-bearing MTDL hit compounds.

[1] Bolognesi, M.L., ACS Medicinal Chemistry Letters 2019, 10.1021/acsmedchemlett.9b00039.

[2] Pisani, L.; Farina, R.; Catto, M.; Iacobazzi, R.M.; Nicolotti, O.; Cellamare, S.; Mangiatordi, G.F.; Denora, N.; Soto-Otero, R.; Siragusa, L.; Altomare, C.D.; Carotti, A., Journal of Medicinal Chemistry 2016, 59, 6791−6806.

[3] Pisani, L.; Iacobazzi, R.M.; Catto, M.; Rullo, M.; Farina, R.; Denora,N.; Cellamare, S.; Altomare, C.D., European Journal of Medicinal Chemistry 2019, 161, 292-309.

[4] Meanwell, N. A., Journal of Medicinal Chemistry 2018, 61 (14), 5822-5880.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

36


Novel Chromane Derivatives for Alzheimer’s Disease

Marques, C.S.,a Bagetta, D.,b Lopez, O.,c Carreiro, E.P.,a Hagenow, S.,d Stark, H.,d Alcaro, S.,b Burke, A.J.a aChemistry Department and Centro de Química de Évora, University of Évora, Rua Romão Ramalho 59, 7000 Évora,

Portugal. b

Dipartimento di Scienze della Salute, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy and

Net4Science Academic Spin-Off, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy. cDepartment of

Organic Chemistry. Faculty of Chemistry, Profesor García González, 1. 41012. Seville, Spain. dHeinrich Heine University

Düsseldorf, Institute of Pharmaceutical and Medicinal Chemistry, Universitaetsstr. 1, 40225 Duesseldorf, Germany.


Heterocyclic units are common in many commercial drugs, within this category those containing a chromane unit are particularly interesting. For example, 4-hydroxy-1-tetralone, a naturally occurring compound isolated from Ampelocera edentula shows activity against cutaneous leishmaniasis and chromanol 293B, a lead compound of potential class III antiarrhythmics can inhibit cardiac IKs potassium channels [1].

With a view to developing such compounds for Alzheimer’s disease treatment we developed a library of chromanol and chromanone compounds that were screened for acetylcholinesterase (AChE), butyrylcholinesterase (BuChE) and both, MAO-A and B activities. Some of the key hit compounds for BuChE inhibition are identified in Fig. 1. In this presentation we will discuss the synthesis and bioassays of these compounds, as well as describing the insights we obtained from molecular docking and STD-NMR.

OH

O

4-Hydroxy-1-tetralone(Leishmaniasis)

O

NO

NC OH

Chromanol 293B(anti-arrhythmics )

(1) IC50 = 6.7µM (eqBuChE) (2) IC50 = 4.0µM (eqBuChE)

O

(3) IC50 = 22 µM (eqBuChE) (eqBuChE)

O

(4) IC50 = 4.8 µM (eqBuChE)

O O

O

O

N

O

OH

O

Figure 1: Biologically active Chromane compounds including our hits for BuChE.

[1] Marques, C.S.; Viana, H.; Correia, C.; Vieira, L.; Galvão, L.P.; Gilmore, K.; Seeberger, P.H.; Burke, A.J. ChemistrySelect, 2018, 3, 11333-11338.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

37


Looking for the Pharmacophore of Benzopyran MAO-B Inhibitors

F. Mesiti,1,2* A. Gaspar,1 D.Chavarria,1 C. Fernandes,1 R. Silva,3 S. Alcaro,2,4 F.Borges1

1CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal;

2Department of “Scienze della Vita”, University “Magna Græcia” di Catanzaro, 88100 Catanzaro, Italy;

3Department of Biological Science, University of Pharmacy, Porto, Portugal;

4 Net4Science srl, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy


Parkinson disease is a neurodegenerative age related disorder mainly characterized by loss of dopaminergic neurons leading to different motors symptoms such as tremor, postural instability and bradykinesia. Drugs nowadays available are palliative and mainly act in order to boost dopamine signaling, e.g. L-Dopa, AADC – inhibitors, Dopamine agonists, COMT and MAO-B inhibitors [1]. Among all, in the last few decades MAO-B inhibitors showed important evidence as disease modifying agents [2]. However, have no evidence from clinical trials.

Then, considering the urgent need of new treatment of PD, the side effects of the drugs in therapy and finally the important properties attributed to MAO-B inhibitors, our project porpoise was the design and development of new MAO-B inhibitors. Furthermore, even if chromone and coumarin [3-5] are well known scaffold to develop MAO-B inhibitors, exist no data in literature about the importance of some chemical feature on benzopyran ring. Moreover, in order to assess the role of benzopyran “O”, carbonyl group and carbon double bond on MAO-B inhibition, four classes of new derivatives were synthesized and biologically evaluated. Furthermore, neurotoxicity studies were performed for the promising compounds. The results obtained will be presented in this communication.

This project is supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, POCI-01-0145-FEDER-029164)). DC and CF grants were also supported by FCT and FEDER/COMPETE and NORTE 2020 funds.

[1] T. Müller, Transl Neurodegener, 2012, 1, 10.

[2] A. H. V. Schapira, CNS Drugs., 2011, 25, 1061-71.

[3] A. Fonseca, J Reis, T Silva, et al., J. Med. Chem., 2017, 60, 7216-7217.

[5] A.Gaspar, M.J. Matos, J. Garrido, et al., Chem Reviews 2014, 114, 4960-4992.

[6] J. Reis, F. Cagide, D. Chavarria, et al., J. Med. Chem 2016, 59, 5879-5893.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

38


Protein-protein interaction studies on thymidylate synthase leads to the identification and characterization of interface inhibitors as anticancer agents. Maria Paola Costi,a Glauco Ponterini,a Gaetano Marverti,a Remo Guerrini,b Salvatore Pacifico,b Stefano

Mangani,c Domenico D’Arca,a A. Lauriola,a Stefania Ferraria aUniversity of Modena and Reggio Emilia, Via Campi 103, 41125-Modena, Italy

bUniversity of Ferrara, Via Fossato di Mortara, 44121 - Ferrara, Italy

cUniversity of Siena, Via A. Moro, 2, 53100-Siena, Italy


Thymidylate synthase is an important target for anticancer therapy [1]. Classical inhibitors as anticancer drugs show rapid drug resistance development. We have identifed the LR octapeptide (Leu-Ser-Cys-Gln-Leu-Tyr-Gln-Arg) as a TS dimer interface binder (allosteric inhibitor) that, by stabilizing the di-inactive TS form, affects protein catalytic activity and increase phosphorylation [2]. The mechanism of action has never been proposed before in 60 years after 5Fluorouracil (5FU) was discovered. LR peptide and derivatives induce cancer cells growth inhibition in platinum-sensitive and -resistant ovarian cancer and other cancer cell models. A combined proteomic-bioinformatic study demonstrates that the different binding site interaction of the peptides compared to known active-site inhibitors (pemetrexed, raltitrexed), shown by X-ray crystal structures and biological studies, causes a different proteome modulation, do not increase TS levels, reduces dhydrofolate reductase (DHFR) and modulates other proteins (HSP90, GARFT, HSP90, TRAP1) in a statistically validated way [3]. This is also true for the proline derivatives that we have designed after the LR peptide [4]. These proteins represent a validated set that can work as biomarkers of the cellular activity. Epithelial ovarian cancer (EOC) shows high levels of folate receptors a (FRa) and therefore we designed experiments to properly conjugate the peptides to enter the cancer cells using the folic acid conjugation. Target engagement studies using a cellular FRET assay was also set up with which we demonstrated that LRpeptide specifically interacts with TS in the cells with high specificity (only 5% of the inhibitor did not bind TS) [5]. The most recent results are related to the design and synthesis of some cyclicP derived from the cyclization of LR peptide and found that out of 10, at least 2 show inhibition of both TS and cancer cell growth. Based on the mechanism as observed form published and preliminary data, the peptide inhibit cancer cell growth mediated by stabilization of the TS di-inactive form that induce increased protein phosphorylation and trigger apoptotic pathway through caspase 3 activation and mitochondrial effect.

1. Cardinale D. et al. Proc Natl Acad Sci US A. 2011, 108:E542-9. 2. Fraczys T. Biochim Biophys Acta. 2015 18541922-1934. 3. Taddia L et J Proteome Res. 2016, 15:3944. 4. P.Saxena et J Med Chem. 2018, 61:7374. 5. Ponterini P et al Sci.Rep. 2016 6:27198.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

39


A candidate multi-targeting approach to block the CD98hc oncoprotein Delia Lanzillotta,a Enrico Iaccino,a Anna Artese,b Selena Mimmi,a Isabella Romeo,b Vincenzo Dattilo,b Sabrina

D’Agostino,a Giosuè Costa,b Eugenio Gaudio,c Stefano Alcaro,b and Francesco Trapassoa. a Dipartimento di Medicina Sperimentale e Clinica,

b Dipartimento di Scienze della Salute, Università “Magna Græcia”di

Catanzaro, Campus “S. Venuta” Loc. Germaneto, 88100-Catanzaro, Italy. c IOR Institute of Oncology Research, 6500-

Bellinzona, Switzerland.


CD98hc is the heavy chain of a transmembrane aminoacid trasporter linked to different light chains (LATs, xCT) by a disulfide bridge [1]. Heteromeric amino acid transporters are involved in cell proliferation, anchorage independence, and tumorigenesis; the role of CD98hc in cancer is also highlighted by its ability to trigger integrin signaling, thus activating downstream effectors such as AKT, FAK, and ERK [2]. We recently found that PTPRJ, a receptor PTP with tumor suppressor activity, interacts with CD98hc and dephosphorylates it. Interestingly, PTPRJ drives CD98hc to proteasomal degradation resulting in a reduction of cell proliferation and apoptosis of lung cancer cells; moreover, patients with the highest CD98hc expression and the lowest PTPRJ expression experience a dismal prognosis [3].

We successfully isolated CD98hc-interacting peptides by a combinatorial phage-display library screening; furthermore, several small molecules putatively targeting the disulfide bridge of the CD98hc heteromeric complex were identified through an in silico screening of a database of chemical compounds. The administration of CD98hc peptides to culture media of A549 lung cancer cells resulted in reduced cell proliferation and apoptosis; these results were paralleled, although to a lower extent, by the small molecules we identified. Interestingly, the combination of peptides and small molecules had a synergistic effect on apoptosis and cell growth inhibition of A549 cells.

Our data suggest CD98hc as a good target for cancer therapy and the development of a combinatorial therapeutic approach targeting different domains of CD98hc might represent a very interesting perspective for the generation of drugs to be used in the clinical setting for the treatment of human cancer with poor prognosis.

Figure 1: Schematic representation of peptides and small molecules targeting CD98hc.

[1] Yan, R. et al. Nature 2019, 568(7750), 127-130.

[2] Feral, C.C. et al. Proc. Natl. Acad. Sci. U. S. A. 2005, 102(2), 355-60.

[3] D’Agostino et al. Oncotarget 2018, 9(34), 23334-23348.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

40


The untranslated region of the BCL2 gene and its noncanonical secondary

structures

C. Cristofari1, C. Sissi1 1Dept. of Pharmaceutical and Pharmacological Sciences, University of Padova, v. Marzolo 5, 35131 Padova,

Italy


Health problems due to cancer diseases are increasing worldwide. Bcl2 is a 239 AA oncoprotein localized on the inner mitochondrial membrane, whose function is to inhibit the apoptotic process. In several pathological processes as liquid and solid cancer, the malignant cells exhibit an evasion from the apoptotic process due to an aberrant activation or an overexpression of this protein. Thus, this has made Bcl2 an interesting target for antineoplastic therapies [1]. The presence of a noncanonical tetrahelical structure resulting from the pairing of four guanines (G-quadruplex or G4) or supported by the formation of C–C+ pairings (i-motif or iM) within its promoter region and their implication on the gene expression is well studied [2,3,4]. However, several computational searches on the 5’-untranslated (UTR) domain revealed the presence of a putative quadruplex-forming sequence (PQS) in the DNA sense strand and also in the primary transcript. Obviously, the presence of PQS in the sense strand implies the presence of a complementary cytosine enriched sequence in the template strand that contains the binding site for the RNA polymerase. As a result, all of these domains can modulate the protein production [5]. In this work we present the first evidence supporting the ability of all of these 25-nt sequences (dBcl2 C- and G-rich sequence and rBcl2-G) to assume, under different experimental conditions (pH, presence of salts and co-solvent), a tetrahelical structure (G4 or iM). Also, in order to confirm that the iM sites could be efficiently targeted by small molecules, we performed a preliminary screening of some derivatives. At present there is no proof supporting that the noncanonical structures within the 5’-UTR region could act as trascriptional or translational switching on/off. However,This work represents the first step to set up a deeper evaluation of the components that could possibly represent the most suitable target in order to realize an advanced and selective silencing strategy for this important oncogene.

[1] Cui, J., and Placzek, W., Int J Mol Sci., 2018, 19(1)

[2] Mergny, J.L., and Sen, D., Chemical Reviews, 2018

[3] Kendrick, S., and Hurley LH., Pre Appl. Chem., 2010, 82(8), 1609-1621.

[4] Sutherland, C; Cui, Y.; Mao, H. and Hurley, L.H., JACS, 2016, 138, 14138-14151.

[5] Sengupta, P.; Chattopadhyay, S.; and Chtterjee, S., Drug Discovery Today, 2017, 8, 1165-1186.

[6] Shahid, R.; Bugaut, A., and Balasubramanian, S., Biochemistry, 2010, 49(38), 8300-8306.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

41


Multi-enzyme inhibitors for the treatment of cancer Serenella Deplano,a Rita Meleddu,a Simona Distinto,a Lisa Sequeira,a Benedetta Fois,a Filippo Cottiglia,a

Claudiu T. Supuran,b and Elias Maccionia. aDepartment of Life and Environmental Sciences, University of Cagliari,Via Ospedale 72, 09124-Cagliari, Italy

bDepartment of NEUROFARBA, Sezione di Scienze Farmaceutiche, Università degli Studi di Firenze, Sesto Fiorentino,

Florence, Italy


Tumours are multifactorial diseases and, as a matter of fact, anticancer chemotherapy is based on the association of drugs directed toward diverse targets of the tumour cells. A promising approach to obtain anticancer agents could be represented by the identification of new small molecules capable to simultaneously inhibit more than one enzyme involved in cancer growth and diffusion.

In this respect, the design of isozyme selective cyclooxygenase and human carbonic anhydrase inhibitors represent a promising route toward the identification of new anti-cancer agents. Indeed, tumours are characterised by both inflammation and hypoxia and both these conditions lead to an altered extracellular pH that, in turns, favour cancer invasion of adjacent tissues.

In this study, starting from a common fragment we have designed and synthesised new molecular entities (Fig 1) that are potential dual inhibitors of both target enzymes. Therefore the design, synthesis, and biological activity of a series of differently substituted benzene sulphonamides have been investigated and the results will be further discussed in this communication.

Figure 1: general structure of the compounds under investigation.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

42


Development of NO-releasing sigma receptor hybrids

as anticancer agents Maria Dichiara, Rosaria Acquaviva, Alfonsina La Mantia, Claudia Di Giacomo, Emanuela Arena, Giuseppe

Floresta, Agostino Marrazzo, Emanuele Amata and Orazio Prezzavento

Department of Drug Science, University of Catania, Viale Andrea Doria 6, 95125-Catania, Italy


Sigma receptors, denoted as sigma-1 and sigma-2 receptor, are involved in several biological and pathological conditions. Both subtypes are highly expressed in human tumors such as breast, colon, ovaries, lung and prostate cancer. A wide number of studies support the use of sigma-1 receptor antagonists and sigma-2 receptor agonists as anticancer agents due to their target-dependent antiproliferative and antiangiogenic effects [1,2].

Nitric oxide (NO) is a Janus-faced molecule with antitumor effects at micromolar concentrations [3]. However, the well-controlled NO administration to biological sites is greatly limited due to its reactive and unstable gaseous nature. For this reason, the use of NO donors is preferred in order to ensure a high and effective NO accumulation into biological systems.

The purpose of this study was to explore and identify novel selective sigma receptors ligands endowed with specific functional profile and combined with a NO-releasing moiety for a synergistic anticancer effect. The new synthesized compounds have been evaluated in in vitro sigma receptors binding assays and tested for their ability to release NO. Preeminent compounds were selected for further in vitro studies on tumorigenic and non-tumorigenic cell lines variously expressing sigma receptors.

n

2−5 meta; para

mX Y

N CH

CH N 0−1

Compd

1−8

9−12

Substitution

meta; para

0

0

XHN

n

Sigma receptor amino moiety with antitumoral activity

Spacer

Tumor cellsdeath

Y

O NO2

NO donor

O

m

Figure 1: General structure of NO-releasing sigma receptor hybrids.

[1] Olivieri, M.; Amata, E.; et al., Journal of medicinal chemistry 2016, 59 (21), 9960-9966.

[2] Amata, E.; Dichiara, M.; et al., Journal of medicinal chemistry 2017, 60 (23), 9531-9544.

[3] Chang, C.F.; Diers, A.R.; Hogg, N., Free radical biology & medicine 2015, 79, 324-336.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

43


Computational tools for multi-target drug discovery

Hanoch Senderowitza a Department of Chemistry, Bar-Ilan University, RAMAT-GAN, 5290002, Israel


The MuTaLig cost action[1] was formulated based on the paradigm that modern, successful drugs should interact with more than a single pharmaceutical target preferably in a synergic fashion. The resulting poly-pharmacology is likely to increase drug efficiency and at the same time reduce the probability for the development of drug resistance. However, this requirement adds another layer of complexity to the drug development process which already involves the simultaneous optimization of multiple parameters (e.g., efficacy, solubility, membrane permeability, metabolic stability, toxicity) some of which are at odds with one another (e.g., solubility and membrane permeability). The development of multi-target drugs could therefore be best formulated as a multi objective optimization problem (MOOP) [2].

Multi objective optimization problems do not have a single solution, i.e., there is no single solution that is better than all other solutions in all objectives. Rather, a set of equally good solutions is typically obtained. In drug discovery this basically means that compounds with different pharmacological profiles are suggested each excelling in one or more (but not all) properties, and it is up to the developer to select the compound with best combination of properties.

The purpose of this seminar is to present the concept of multi objective optimization as it is related to the different stages of the drug discovery process (hit identification and lead optimization) and the computational tools used to address it. Selected examples from the literature as well as from the work performed within the framework of the MuTaLig Cost Action will be presented. The role of databases such as ChEMBL and the MuTaLig-generated Chemotheca [3] will be highlighted.

1. http://www.mutalig.eu/

2. Nicolaou, CA., Brown, N., Pattichis, CS. Molecular optimization using computational multi-objective methods. Curr. Opin. Drug Discov. Devel. (2007) 10 316.

3. Ortuso, F., Bagetta, D., Maruca, A., Talarico, C., Bolognesi, M.L., Borges, F., Bryant, S.D., Langer, T., Senderowitz, H., and Alcaro, S. The Mu.Ta.Lig. Chemotheca: A Community-Populated Molecular Database for Multi-Target Ligands Identification and Compound-Repurposing. Front. Chem. (2018) 6, 130.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

44


In silico methods for multi-target drug development

Agnieszka A. Kaczor,a,b and Monika Pituchac a Department of Synthesis and Chemical Technology of Pharmaceutical Substances, Medical University of Lublin, 4A

Chodzki St., PL-20093 Lublin, Poland b School of Pharmacy, University of Eastern Finland, Yliopistonranta 1, FI-70211 Kuopio, Finland

cIndependent Radiopharmacy Unit, Department of Organic Chemistry, Medical University of Lublin, 4A Chodzki St., PL-

20093 Lublin, Poland


Polypharmacology is nowadays considered an increasingly crucial aspect in discovering new drugs as a number of original single-target drugs was far behind the expectations during last ten years. Classical approaches to design multi-target drugs (MTDs) involve three different ways of combination of two pharmacophores, leading to a cleavable conjugate where two pharmacophores are connected by a linker (a modern form of combination therapy), a compound with overlapping pharmacophores or a highly integrated multi-target drug. Multi-target drugs, in particular those obtained by pharmacophore integration strategy are referred to as “master key compounds”. Thus, MTDs are designed broadly as hybrid or conjugated drugs or as chimeric drugs from two or more pharmacophores/drugs having specific pharmacological activities [1].

Here we present our experience in using in silico approaches to design multi-target compounds. The first example involves tailored structure-based virtual screening which resulted in identification of 10 multi-target ligands of aminergic GPCRs [2] with confirmed in vitro affinity and functional activity as well as interesting properties in vivo [2,3]. Two next examples rely on application of PASS and Pharma Expert software which are commonly used for target identification and drug repositioning. Using these tools we identified novel thiosemicarbazide derivatives with 4-nitrophenyl group as multi-target drugs: α-glucosidase inhibitors with antibacterial and antiproliferative activity and confirmed these activities experimentally [4]. In another project we applied PASS and Pharma Expert to decipher the mechanism of anticancer activity of novel 1,2,4-triazole derivatives as inhibition of CK1γ and CK2α protein kinases and also verified this hypothesis in vitro.

[1] Kondej, M.; Stepnicki, P.; Kaczor, A.A. International Journal of Molecular Sciences 2018, 19 (10), pii: E3105.

[2] Kaczor, A.A.; Silva, A.G.; Loza, M.I.; Kolb, P.; Castro, M.; Poso, A. ChemMedChem 2016, 11 (7), 718-729.

[3] Kaczor, A.A.; Targowska-Duda, K.M.; Budzynska, B.; Biala, G.; Silva, A.G.; Castro, M. Neurochemistry International 2016, 96, 84-99.

[4] Wos, M.; Miazga-Karska, M.; Kaczor, A.A.; Klimek, K.; Karczmarzyk, Z.; Kowalczuk, D.; Wysocki, W.; Ginalska, G.; Urbanczyk-Lipkowska, Z.; Morawiak, M.; Pitucha, M. Biomedicine and Pharmacotherapy 2017, 93, 1269-1276.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

45


Combined FAAH and COX inhibition by Flurbiprofen amide derivatives for the treatment of pain and inflammation

Federica Moraca,a Carmine Marco Morgillo,b Alessandro Deplano,c Ettore Novellino,a Valentina Onnis,c Christopher J. Fowlerd and Bruno Catalanottia

a Department of Pharmacy, University “Federico II” of Naples, via D. Montesano 49, 80131-Naples, Italy.

b Institute of Analytical Sciences, University Claude Bernard Lyon I (UCBL), rue de la DOUA, 69100-Villeurbanne, France.

c Department of Life and Environmental Sciences – Unit of Pharmaceutical, Pharmacological and Nutraceutical

Sciences, University of Cagliari, Via Ospedale 72, 09124-Cagliari, Italy. d Department of Pharmacology and Clinical Neuroscience, Umeå University, Umeå, Sweden.


Nonsteroidal anti-inflammatory drugs (NSAIDs) – such as ibuprofen and flurbiprofen – are non-selective COX inhibitors widely used to treat acute and chronic pain. Several studies have indicated that the analgesic effect of NSAIDs is enhanced when administered in combination with drugs that inhibit also the fatty acid amide hydrolase (FAAH) [1], an enzyme that degrades endocannabinoid anandamide (AEA), greatly decreasing the severity of GI side effects. From these evidences, arised the rational basis for the design of multi-target FAAH/COX inhibitors [2]. A series of ibuprofen and flurbiprofen amides derivatives have been previously designed as dual FAAH/COX inhibitors and, among them, ibu-am5 and flu-am1 revealed an interesting dual-action, retaining similar COX-inhibitory properties and an increased inhibition of FAAH than the parent compounds [3]. Here, we present the design, molecular modelling and in vitro and in vivo evaluation of a small series of flu-am1 analogs (Figure 1) with an increased dual FAAH/COX inhibition as promising compounds in the treatment of pain and inflammation.

Figure 1: Multi-target strategy to design Flurbiprofen amide derivatives as analgesic compounds.

[1] Bracey, M.H.; Hanson, M.A.; Masuda, K.R.; Stevens, R.C.; Cravatt, B.F., Science 2002, 298 (5599), 1793–1796.

[2] Holt, S.; Paylor, B.; Boldrup, L.; Alajakku, K.; Vandevoorde, S.; Sundström, A.; Cocco, M.T.; Onnis, V.; Fowler, C.J., European Journal of Pharmacology 2007, 565 (1-3), 26-36.

[3] Karlsson, J.; Morgillo, C.M.; Deplano, A.; Smaldone, G.; Pedone, E.; Luque, F.J.; Svensson, M.; Novellino, E.; Congiu, C.; Onnis, V.; Catalanotti, B.; Fowler, C.J., PLoS One 2015, 10 (11), e0142711.

FAAH COXs

Flu-am1

X

BOOK of ABSTRACTS

MedChem2019




-15th

2019

46


On the inhibition mechanism of glutathione transferase p1 by piperlongumine. Insight from theory.

Mario Prejanò,a Tiziana Marino,a and Nino Russoa a Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Via Pietro Bucci, 87036-Rende (CS), Italia


Piperlongumine (PL) is an anticancer compound whose activity is related to the inhibition of human glutathione transferase of pi class (GSTP1) overexpressed in cancerous tumors and implicated in the metabolism of electrophilic compounds. In the present work, the inhibition mechanism of hydrolyzed piperlongumine (hPL) has been investigated employing QM and QM/MM levels of theory, starting from the recent deposited X-ray structure (PDB code: 5J41) [1] presenting the covalent bond between hPL and glutathione (GSH) . The potential energy surfaces (PESs) underline the contributions of Tyr residue close to G site in the catalytic pocket of the enzyme. [2] The proposed mechanism occurs through a one-step process represented by the nucleophilic addition of the glutathione thiol to electrophilic species giving rise to the simultaneous C-S and H-C bonds formation. Both the used methods give barrier heights (19.8 and 21.5 kcal mol-1 at QM/MM and QM, respectively) close to that experimentally measured for the C-S bond formations. (23.8 kcal mol-1)

Figure 1: Schematic mechanism of inhibitor action.

[1] Harshbarger, W., Gondi, S., Ficarro, S.B., Hunter, J., Udayakumar, D., Gurbani, D., Singer, W.D.; Liu, Y.; Li, L.; Marto, J.A., Journal of Biological Chemistry 2017, 292, 112–120.

[2] Prejanò, M.; Marino, T.; Russo, N., Frontiers in chemistry 2018, 6, 606.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

47


In silico repurposing of the hexahydrocyclopenta[c]quinoline scaffold as potent

Carbonic Anhydrase inhibitors

Annachiara Tinivella,a,b Anna Laura Benatti,a Luca Pinzi,a and Giulio Rastelli*,a a Department of Life Sciences, University of Modena and Reggio Emilia, Via Giuseppe Campi 103, 41125, Modena, Italy.

b Clinical and Experimental Medicine PhD Program, University of Modena and Reggio Emilia, Modena, Italy


Drug repurposing is as an established drug discovery process by which novel therapeutic indications can be identified for already marketed drugs or candidates under clinical evaluation [1]. This allows for the efficient exploitation of molecules that already proved, in most cases, to possess satisfactory pharmacokinetic characteristics and toxicity profiles, and optimized formulation properties. In recent times, novel interesting opportunities for drug repurposing arose from the increase of publicly available biological and chemical data. In this context, integrated in silico approaches have proven to be efficient strategies to analyze such amounts of information and predict the activity of known ligands for new targets [2].

In this study, an integrated in silico protocol was developed to identify possible novel uses for a library of previously identified molecules with an interesting hexahydrocyclopenta[c]quinoline scaffold and low molecular weight [3]. Different 2D fingerprint-based (ECFP4 and MACCS) and 3D shape-based (ROCS) approaches were applied to subject this dataset to extensive ligand-based analyses against the DrugBank database. Results of the ligand-based analyses unveiled a high degree of similarity for some of the investigated compounds against Carbonic Anhydrase (CA) inhibitors. Molecular docking of the best-scoring ligands was performed into the active site of representative crystal structures of different CA isoforms reported into the Protein Data Bank.

The overall results led to the selection of one promising candidate compound for in vitro testing, which resulted to be a low nanomolar inhibitor of CA II. Further design based on the hexahydrocyclopenta[c]quinoline scaffold is currently in progress using machine learning models trained on a dataset of known selective CA inhibitors.

[1] Ashburn, T. T.; Thor, K. B. Nature Reviews Drug Discovery 2004, 8 (3), 673–683.

[2] March-Vila, E.; Pinzi, L.; Sturm, N.; Tinivella, A.; Engkvist, O.; Chen, H.; Rastelli, G. Front Pharmacol 2017, 8, 298.

[3] L. Carlino, M. S. Christodoulou, V. Restelli, F. Caporuscio, F. Foschi, M. S. Semrau, E. Costanzi, A. Tinivella, L. Pinzi, L. Lo Presti, R. Battistutta, P. Storici, M. Broggini, D. Passarella, G. Rastelli, ChemMedChem 2018, 24 (13), 2627

BOOK of ABSTRACTS

MedChem2019




-15th

2019

48


Marie Skłodowska-Curie Actions – mobility and training for researchers Frank Marx

Deputy Head of Unit

Research Executive Agency

Unit: Marie Skłodowska-Curie COFUND, Researcher’s Night and Individual Fellowships: Global


The Marie Skłodowska-Curie Actions (MSCA) support excellent researchers at all stages of their careers and from all scientific disciplines through training and mobility opportunities. The presentation provides for an overview of the actions and some hints for successful applications.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

49


The Innovative Medicines Initiative: Europe’s partnership for health Gianluca Sbardella

a Università di Salerno, Dipartimento di Farmacia, EpigeneticMedChemLab

Via Giovanni Paolo II, 132 - 84084, Fisciano (SA) Italy

tel. +39 089 969770 Email: [email protected]

BOOK of ABSTRACTS

MedChem2019




-15th

2019

50


Calabria regional policies for research and innovation Menotti Lucchetta

Regione Calabria, Research and Innovation Unit


The Calabria Region supports research and innovation policies in its territory by implementing the 2014-2020 Regional Operational Program.

The program includes two investment priorities, one dedicated to research infrastructures and the other to support for businesses and universities.

The implementation of the Program was preceded by the definition of the smart specialization strategy which identified a limited number of innovation areas on which to focus investments. Among these, the one dedicated to life sciences has been identified.

Regional support for research and innovation policies comes with many tools: collaborative projects between companies and universities for industrial research and experimental development, innovation services for SMEs, start-ups and research spinoffs , Innovation Clusters, support for the participation of businesses in H2020 programme, support for research infrastructures and industrial validation projects for research results.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

51


Exploitation of Research Results: European fund and network

Antonio Mazzei

CalabriaInnova, Fincalabra, loc. Campo, 88040- Settingiano (CZ), Italy


The exploitation of the researches' results [1] is based on the development of a market strategy including the identification of financing channels. When this process starts, it is necessary to think about "what need I

can satisfy, who can be interested in buying my product, which commercial channels should I start and how

should I disseminate my results". All these elements can be summarized in only one word "Impact". The term "Impact" means not only the capacity of innovation, but it involves also the creation of new markets, the development of new opportunities, the strengthening of competitiveness, the growth of the territory and bringing other important benefits for society [2]. Promoted by the European Commission, within the Award Criteria (Excellence, Impact, and Implementation), it was the central element of the transition from the 7th framework program to Horizon 2020 and is confirmed in the 9th framework program (Horizon Europe).

Fincalabra SpA operates in this context supporting the growth of the regional territory and operating in order to achieve the match between research and enterprises.

The overall vision of Horizon Europe shows that the topic "health" will play an important role in the program. In H2020 the impact was intended as action on society, in terms of social, economic or environmental effects. In Horizon Europe there will be the concept mission involving the whole community. The projects will require a strategic, intra-sectoral network, able to have a high impact on the territory both in terms of geographical extension and in terms of the multidisciplinary skills involved. In HEurope the term health appears many times. Specific mission is co-designed with Member States, stakeholders, and citizen and programmed within the Global Challenge and Industrial Competitiveness pillar (7.7 billion €). 1-Health throughout the life course, 2- Environmental and Social Health, 3-Non-communicable and Rare disease, 4-Infectious Diseases, 5-Digital solutions for health and care. The contribution shows how “the concept of network changes” and which funding channels will be available in the period 2021-2027.

[1] https://ec.europa.eu/research/participants/data/ref/h2020/other/events/2018-09-21/9_dissemination-exploitation-activities_en.pdf

[2] https://www.healthncp.net/horizon-2020

BOOK of ABSTRACTS

MedChem2019




-15th

2019

52

Paul Ehrlich & MuTaLig Poster Communications

BOOK of ABSTRACTS

MedChem2019




-15th

2019

53

Paul Ehrlich & MuTaLig Poster Communications 1 (PC_1)

X-ray crystal structure of carbonic anhydrase XII complexed with a theranostic monoclonal antibody fragment

Davide Esposito,a,b Martina Buonanno,a Simona Maria Monti,a Claudiu T. Supuran,c Reinhard Zeidler,d Giuseppina De Simonea and Vincenzo Alterioa

a Istituto di Biostrutture e Bioimmagini, CNR, Naples, Italy

b University of Sannio, Benevento, Italy

cLaboratorio di Chimica Bioinorganica, Università degli Studi di Firenze, Sesto Fiorentino (Firenze), Italy

d Department of Gene Vectors, Helmholtz Center for Environmental Health, Munich, Germany


Human Carbonic Anhydrases (hCAs) are ubiquitous metallo-enzymes present in prokaryotes and eukaryotes, which efficiently catalyze the reversible hydration of carbon dioxide to bicarbonate ion and proton [1]. Among the 15 isoforms so far described in humans, hCA XII is an interesting diagnostic and therapeutic target, since it has been demonstrated to be over-expressed in many tumors and associated with cancer progression and metastasis [2]. Due to these features, hCA XII has been the object of numerous studies focused to the development of anticancer drugs, with promising results recently achieved by Zeidler’s group, that developed a monoclonal antibody (6A10), which has been demonstrated to efficiently inhibit hCA XII enzymatic activity in vitro [3] and in intact cells [4]. Notably, 6A10 reduces the growth of cancer cells in vitro and in a xenograft lung carcinoma model, with a postulated mode of action directly dependent from inhibition of hCA XII catalytic activity [4].

Due to the promising features of 6A10, a recombinant antigen-binding fragment (Fab) of this antibody (Fab6A10), has been developed. Indeed, the usage of antibody fragments has several advantages compared to full IgG monoclonal antibodies including a greater stability in serum and a lower immunogenicity [5,6].

Here, a biochemical and structural characterization of Fab6A10 is reported. Binding and kinetic assays demonstrated that Fab6A10 is highly specific towards hCA XII, while the crystallographic structure of hCA XII/Fab6A10 complex provided molecular insights into the inhibition mechanism of Fab6A10.

This work was supported by the Italian MIUR, through the PRIN project 201744BN5T.

[1] Supuran, C. T. Nature reviews. Drug discovery 2008, 7 (2), 168-181.

[2] Supuran, C. T.; Alterio, V.; Di Fiore, A.; D’Ambrosio, K.; Carta, F.; Monti, S. M.; De Simone, G. Medicinal research reviews 2018, 38 (6), 1799-1836.

[3] Battke, C.; Kremmer, E.; Mysliwietz, J.; Gondi, G.; Dumitru, C.; Brandau, S.; Lang, S.; Vullo, D.; Supuran, C.; Zeidler, R. Cancer immunology, immunotherapy 2011, 60 (5), 649-658.

[4] Gondi, G.; Mysliwietz, J.; Hulikova, A.; Jen, J. P.; Swietach, P.; Kremmer, E.; Zeidler, R. Cancer research 2013, 73

(21), 6494-6503.

[5] Holliger, P.; Hudson, P. J. Nature biotechnology 2005, 23 (9), 1126-1136.

[6] Nelson, A. L. mAbs 2010, 2 (1), 77-83.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

54


Compounds Targeting the RNA-Binding Protein HuR. Structure-Based Design, Synthesis and Interaction Studies.

Francesca Alessandra Ambrosio,a Giosuè Costa,a Serena Della Volpe,b Francesca Vasile,c Stefano Alcaro,a Simona Collinab

a Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Viale Europa, 88100, Catanzaro, Italy

b Department of Drug Sciences, Medicinal Chemistry and Technology Section, University of Pavia, Via Taramelli 12,

27100, Pavia, Italy c Department of Chemistry, University of Milan, Via Golgi 19, 20133, Milano, Italy


The key role of RNA-binding proteins (RBPs) in regulating post-transcriptional processes and their involvement in several pathologies such as cancer and neurodegeneration, have highlighted their potential as therapeutic targets. Among RBPs, the family of Embryonic Lethal Abnormal Vision proteins is involved in controlling the functional activities of diverse RNA populations. In particular, HuR is considered a valid drug target for anticancer therapy, so compounds able to modulate the HuR−RNA complex stability may have anticancer properties [1]. Here, we present the rational design and synthesis of structurally novel HuR ligands, potentially acting as HuR−RNA interferers. Starting from the 4ED5 pdb model [2], molecular modeling studies were performed in order to investigate the protein rearrangement and the theoretical binding affinity of the studied compounds versus HuR protein. Combining STD, NMR and in silico studies, we provide a guide for further research on the development of new effective HuR−RNA complex interfering compounds.

Figure 1: 3D representation of HuR-RNA complex; the protein and the RNA are showed as light orange and orange

cartoon, respectively.

[1] Filippova, N.; Yang, X.; Ananthan, S.; Sorochinsky, A.; Hackney, J.; Gentry, Z.; Bae, S.; King, P.; Nabors, L. B., Journal of Biological Chemistry 2017, 292, 16999−17010.

[2] Wang, H.; Zeng, F.; Liu, H.; Niu, L.; Teng, M.; Li, X., Acta Crystallographic Section D Structural Biology 2013. 69, 373-

80.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

55


Benzothienoquinazolinones as new inhibitor of Topoisomerases and Tubulin

Alexia Barbarossa,a Jessica Ceramella,a Anna Caruso,a Maria Antonietta Occhiuzzi,a Domenico Iacopetta,a Carmela Saturnino,b Fedora Grande,a Bruno Rizzuti,c and M. Stefania Sinicropia

a Dep. of Pharmacy, Health and Nutritional Sciences, University of Calabria, Arcavacata di Rende, Italy;

b Dep. of Science, University of Basilicata, Potenza, Italy

c CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF. Cal, Dep. of Physics, University of Calabria, Via P. Bucci, 87036 Rende

(CS), Italy


Ellipticine is a naturally occurring alkaloid with a carbazole backbone, well known for their antitumor activities, exerted through DNA intercalation, high DNA binding affinity and inhibition of the topoisomerases [1]. However, because of onset of some side effects the therapeutic application of Ellipticine and its derivatives used in clinic therapy, still remain limited [2]. Accordingly, with the aim to reduce side effects and improving their biologic activities, the search for new Ellipticine analogues is always demanded.

This work is focused on the creation of new library of benzothienoquinazolinones (4-9), analogues of Ellipticine, in which both the carbazole moiety and the pyridine ring were replaced by a dibenzothiophene- and a pyrimidine moiety, respectively. The synthesis of these 3-(alkyl(dialkyl)amino)benzothieno[2,3-f]quinazolin-1(2H)-ones) was realized in a simple one-pot reaction using 3-aminodibenzothiophene as a starting material (Figure 1).

These have shown an interesting anti-proliferative activity on two breast cancer cell lines, MCF-7 and MDA-MB-231. Molecular docking of these compounds was performed on the crystallographic enzyme structures of Tubulin, Topoisomerase I and II. The simulation results showed that the compounds investigated bind the enzymes with a relatively high affinity, at least in the low micromolar range. Other in vitro assays are in progress to confirm the in silico results.

S NH

NN

R1

R

O

4-9 Figure 1: Benzothienoquinazolinones.

[1] Kizek R.; Adam V.; Hrabeta J.; Eckschlager T.; Smutny S.; Burda J.V.; Frei E.; Stiborova M., Pharmacol. Ther 2012,

133, 26–39.

[2] Caruso A.; Iacopetta D.; Puoci F.; Cappello A. R.; Saturnino C.; Sinicropi M. S., Mini Review in Medicinal Chemistry

2016, 6 (8), 630-43.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

56


Design, synthesis and pharmacological characterization of novel potent non-

steroidal agonists of the farnesoid X receptor

Valentina Sepe,a Claudia Finamore,a Giuliana Baronissi,a Francesco Saverio Di Leva,a Chiara Cassiano,d Maria Chiara Monti,d Ettore Novellino,a Vittorio Limongelli,a,c Stefano Fiorucci,b Angela Zampellaa

a Department of Pharmacy, University of Naples “Federico II”, via D. Montesano 49, 80131 Naples, Italy

b Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, Perugia, Italy

c Università della Svizzera Italiana (USI), Faculty of Biomedical Sciences, Institute of Computational Science-Center for

Computational Medicine in Cardiology, Via G. Buffi 13, CH-6900 Lugano, Switzerland d

Department of Pharmacy, University of Salerno, Via Giovanni Paolo II, 132, 84084 Fisciano, Salerno, Italy


Activation of FXR receptor has shown effective in several liver injury. In this study, starting from GW4064, the first non-steroidal FXR ligand [1], we have elaborated and synthesized a library of derivates in order to improve the agonistic activity on FXR and the ADME properties. Maintaining the central isoxazole core with the 2,6-dichloro-substituted phenyl moiety at C-3 and the isopropyl group at C-5 we have introduced on the oxymethylene at C-4 different phenols using Mitsunobu reactions. The pharmacological characterization and molecular docking studies for the structure−acqvity raqonalizaqon, allowed the idenqficaqon of

several FXR agonists. Compound 17 has been proved the most promising lead of this library, combining good pharmacokinetic properties with interesting FXR activity in vivo, and preventing acetaminophen-induced liver injury in mice [2],[3].

Figure 1. A) Steroidal and non-steroidal FXR agonists in advanced clinical trials; B) the most promising non-steroidal synthetic derivative from this study

[1] Maloney, P. R. et al., J. Med. Chem. 2000, 43, 2971−2974.

[2] Lee, F. Y. et al., Mol. Endocrinol. 2010, 24, 1626−1636.

[3] Sepe, V. et al., ACS Med. Chem. Lett., 2018, DOI: 10.1021/acsmedchemlett.8b00423

BOOK of ABSTRACTS

MedChem2019




-15th

2019

57


Hydroxypyridin-4-ones are a versatile scaffold to develop copper(II)-chelating COMT inhibitors with neuroprotective properties

Tiago Barros Silva,a,b Carlos Fernandes,b Lisa Sequeira,b Vera Silva,b,c Renata Silva,c Patrício Soares-da-Silvae

and Fernanda Borgesb a CNC – Center for Neuroscience and Cell Biology, University of Coimbra, UC Biotech, Biocant Park, 3060-197,

Cantanhede, Portugal b CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre s/n,

4169-007, Porto, Portugal c UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of

Porto, Rua Jorge de Viterbo Ferreira 228, 4050-313, Porto, Portugal d Department of Biomedicine, Unit of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto,

Alameda Prof. Hernani Monteiro, 4200-319, Porto, Portugal


Catechol O-methyltransferase (COMT) inhibitors are valuable co-adjuvant drugs in the clinical management of Parkinson’s disease [1]. Standard COMT inhibitors are based on the nitrocatechol scaffold, which chelates the Mg co-factor within COMT and lead to a tight-binding inhibition mechanism. While effective, these drugs have been linked to drug-induced hepatoxicity and poor brain bioavailability [2]. In our study, we explored alternative scaffolds that mimic the pharmacological behavior of nitrocatechols under physiological conditions and focused our strategy on hydroxypyridin-4-ones [3]. The rationale for this approach is to develop COMT inhibitors lacking the nitro group, circumventing the risk of nitrocatechol-induced toxicity. We prepared a small library of new hydroxypyridin-4-ones and screened their ability to inhibit COMT from rat liver homogenates. We found that the N-aryl substitution pattern led to a significant increase in COMT inhibition, particularly for the 3’,4’-dimethyl derivative TS22. When we traced the UV/Vis spectra of our derivatives in presence of divalent metals we found a selective chelation of copper(II) over iron(II) and magnesium(II). We screened TS22 in a vast array of cell lines (differentiated SH-SY5Y, Caco-2, SU-DHL-10, WSU-DLCL2, VAL, U2932, SU-DHL-2) and found that TS22 did not lead to a significant loss in cell viability at 25 µM. Moreover, TS22 (12.5 and 25 µM) effectively rescued differentiated SH-SY5Y from H2O2-induced cell death. The results obtained so far will be presented in this panel communication.

This project is supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, POCI-01-0145-FEDER-029164, and NORTE-01-0145-FEDER-000028). TS (SFRH/BPD/114945/2016), CF and VS grants were also supported by FCT and FEDER/COMPETE and NORTE 2020 funds.

[1] Spahr, L.; Rubbia-Brandt, L.; Burkhard, P.R.; Assal, F.; Hadengue, A. Digestive Diseases and Sciences 2000, 45

(9):1881-1884. [2] Parashos, S.A., Wielinski, C.L.; Kern, J.A. Clinical Neuropharmacology 2004, 27 (3), 119-123. [3] Robinson, R.G.; Smith, S.M.; et al. ACS Chemical Neuroscience 2012, 3 (2), 129-140.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

58


Study of pyrazolo[3,4-b]pyridin-6-one and pyrazolo[3,4-b]-pyridine scaffolds as

MNK inhibitors

Elisabeth Bou-Petit,1,* Helena Alarcón,1 Pedro Jesús Guijarro,2 Stefan Hümmer,2 Roger Estrada,1 Santiago Ramón y Cajal2 and José I. Borrell1.

1 Grup de Química Farmacèutica (GQF), IQS School of Engineering, Universitat Ramon Llull, Barcelona, Spain

2 Anatomía Patológica, Hospital Universitario Valle de Hebrón, Universidad Autónoma de Barcelona, Spain


Overexpression eukaryotic initiation factor 4E (eIF4E) has been described in many types of cancer. Elevated levels of phosphorylated eukaryotic initiation factor 4E (eIF4E) have been detected in many tumor types. MAP kinase interacting kinases 1/2 (MNK1/2) regulate the function of eIF4E through phosphorylation in the conserved Ser209 and while this phosphorylation is necessary for oncogenic transformation, seems to be dispensable for normal development1. For this reason, the pharmacological inhibition of MNKs may provide non-toxic and effective therapeutic strategy for the treatment of cancer2.

Here we study the suitability of two new scaffolds as MNK inhibitors: pyrazolo[3,4-b]pyridin-6-ones and pyrazolo[3,4-b]pyridines. Up to 5 families of compounds derivates of such structures have been synthetized and tested. Three hits have been identified as dual inhibitors with an interesting potency and selectivity. The potential of this candidates has been demonstrated in vitro on triple negative breast cancer cell lines with promising results.

HN

N

NO

R1

R2R4

N

N

NR4

R1

R2R4

1 2

R3 R3

Figure 1. General scaffolds studied as MNK inhibitors

1. Ueda, T.; Watanabe-Fukunaga, R.; Fukuyama, H.; Nagata, S.; Fukunaga, R., Molecular and Cellular Biology 2004, 24, 6539–6549.

2. Diab, S. et al., Chemistry & Biology 2014, 21, 441–452.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

59


3’-Deoxy-3’-fluoro-7-deazapurine nucleosides: synthesis and evaluation against kinetoplastid parasites

Jakob Bouton,a Fabian Hulpia,a Louis Maes,b Guy Caljon,b Serge Van Calenbergha aLaboratory for Medicinal Chemistry (FFW), Ghent University, Ottergemsesteenweg 460, 9000 Ghent, Belgium

bLaboratory of Microbiology, Parasitology and Hygiene (LMPH), University of Antwerp, Universiteitsplein 1, B-

2610,Wilrijk, Belgium.


Sleeping sickness, Chagas disease and Leishmaniasis are classified by the WHO as “neglected tropical diseases”. They are vector-borne diseases that affect millions of people in the poorer parts of the world and are often fatal if left untreated. Their causative agents are the kinetoplastid parasites Trypanosoma brucei, Trypanosoma cruzi and Leishmania spp., respectively. Current therapies suffer from severe drawbacks such as toxicity, administration difficulties and low efficacy, highlighting the need for novel efficient drugs. Like most protozoan parasites, the kinetoplastids are purine auxotrophs and rely on the purine salvage pathway as their sole purine source. Interfering with that salvage pathway is therefore an attractive strategy for the development of new chemotherapeutic agents.

Recently, our group discovered several new nucleoside analogues, derived from the natural product tubercidin (7-deazadenosine) with promising activity against these parasites. Modifications of the sugar (3’-deoxygenation) and C7-substitutions of the nucleobase led to highly potent analogues with reduced toxicity.1,2 In this work we wanted to further investigate modifications of the ribose part. 3’-Deoxy-3’-fluoroadenosine and 3’-deoxy-3’-fluoroinosine have previously been described as antiprotozoal agents.3 We therefore combined the 3’-deoxy-3’-fluoro-ribose moiety with a 7-deazapurine nucleobase surrogate. Several substituents were introduced on the C7-position and the C2- and C6-position were appropriately derivatized to furnish a collection of adenosine, inosine and guanosine mimics.

The synthesized nucleosides were assayed in vitro against T. brucei, T. cruzi and L. Inf. Several compounds displayed interesting activity, warranting further evaluation in vivo.

O NHO

N N

X

R

F OH

- 30 compounds- various C7 substituents

- nM-µM IC50 T. cruzi, T. brucei, L. inf

Y

X = NH2, OMe, OHY = NH2, H

1. Hulpia F. et al. Eur. J. Med. Chem. 2019, 164, 689-705

2. Hulpia F. et al. J. Med. Chem. 2018, 61(20), 9287-9300

3. JP63008334, 1988

BOOK of ABSTRACTS

MedChem2019




-15th

2019

60


Development of new antibiotics based on natural scaffolds

Fernando Cagide,a Catarina Oliveira,a Sofia Benfeito,a Carlos Fernandes,a Alexandra Gaspara and Fernanda Borgesa

a CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal


Nowadays, antibiotics are indispensable to treat bacterial infections. However, resistance of bacteria to conventional antimicrobial (antibacterial, antiparasitic and antifungal) drugs is a fast-growing problem, causing millions of deaths every year and demanding seeking new antibiotics.

In this context, in 2017, the World Health Organization (WHO) issued a global priority pathogen list to guide efforts to find new antibiotics against the current public health bacterial threats. Gram-positive bacterial pathogens, such as Staphylococcus aureus, Streptococcus pneumoniae, and Enterococcus faecium, are responsible for community-acquired and hospital-associated infections and are an increasing public health threat. For these reasons, there is an urgent need for new antimicrobial and therapeutic strategies to deal with the ever-evolving antimicrobial resistance among the most prevalent bacterial pathogens.

Therefore, the aim of this project has been focused on the design and synthesis of innovative phosphonium salts as antibiotics. In order to achieve this goal, structural changes were performed in natural phenolic antioxidants present in human diet (as benzoic and cinnamic acids) by inserting an aliphatic carbon chain spacer linked to a triphenylphosphonium cation (TPP+). These natural scaffolds are widely distributed in plants and fruit and display a great structural variety. In addition, a wide range of pharmacological activities of these natural compounds as well as of some quaternary phosphonium salts, as antimicrobial and/or enzymatic inhibition properties [1-3] have been reported.

The results obtained so far will be presented in this communication.

This project was supported by UID/QUI/00081/2019, FEDER/COMPETE POCI-01-0145-FEDER-028397 and Norte-01-0145-FEDER-000028 grants. C. Oliveira, S. Benfeito, C. Fernandes, A. Gaspar were also supported by FCT and FEDER/COMPETE and NORTE 2020 funds. We also thank CO-ADD (The Community for Antimicrobial Drug Discovery), funded by the Welcome Trust (UK) and The University of Queensland (Australia) for performing antimicrobial screening of compounds.

[1] Oliveira, C.; Cagide, F.; Teixeira, J.; Amorim, R.; Sequeira, L.; Mesiti, F.; Silva, T.; Garrido, J.; Remião, F.; Vilar, S.; Uriarte, E.; Oliveira, P.J.; Borges, F., Frontiers in Chemistry, 2018, 6, 126.

[2] Teixeira, J.; Oliveira, C.; Amorim, R.; Cagide, F.; Garrido, J.; Ribeiro, J.A.; Pereira, C.M.; Silva, A.F.; Andrade, P.B.; Oliveira, P.J.; Borges, F., Scientific Reports, Nature, 2017, 7, 6842.

[3] Benfeito, S.; Oliveira, C.; Soares, P.; Fernandes, C.; Silva, T.; Teixeira, J.; Borges, F., Mitochondrion, 2013, 13, 427-435.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

61


Metabolites prediction at the Mu.Ta.Lig. Chemotheca Raffaella Catalano,a,b Francesco Ortusoa,b

aDipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Campus “S. Venuta” Viale Europa,

88100, Catanzaro, Italy bNet4Science srl, Università “Magna Græcia”, Campus “S. Venuta” Viale Europa, 88100, Catanzaro, Italy


Xenobiotic metabolism plays a key role in the drug discovery process. In silico approaches are increasingly used to predict the metabolic conversion of drugs allowing costs lowering, time savings, and thus decreased the failure in late discovery phases [1]. Indeed, metabolic transformations may modulate the bioactivity of a certain compound by reducing or increasing its therapeutic properties. These effects can be exploited through the development of prodrugs, but they can also lead to toxic agents (Figure 1).

There are different approaches for predicting xenobiotic metabolism: (i) site of metabolism (SoM) prediction, (ii) metabolite structure prediction, and (iii) prediction of the interaction of metabolites with metabolic enzymes. Numerous software is available for the purposes described [2].

A rule-based tool for the prediction of metabolites is Sygma [3] (Systematic Generation of potential Metabolites), developed by Organon (now Schering-Plough) and released as open source code. This software is currently used to calculate the phase I and II metabolites structure of all Mu.Ta.Lig. Chemotheca stored molecules [4]. This code is going to be implemented as a new molecular descriptor for the Chemotheca registered user.

Figure 1: Biological metabolites behavior.

[1] Kazmi S R, et al., Computers in biology and medicine 2019.

[2] Tan L, and Kirchmair J, Drug Metabolism Prediction. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. 2014; 27-

52.

[3] Ridder L, Wagener M, ChemMedChem 2008; 3 (5):821-832.

[4] http://chemotheca.unicz.it

METABOLITE

Toxic for different organs in the body

Inactive towards biological target

More active than substrate towards

biological target PRODRUG

BOOK of ABSTRACTS

MedChem2019




-15th

2019

62


Interesting biological properties of Anchusa azurea Mill. (Boraginaceae) methanol

extract

Jessica Ceramella,a Monica Rosa Loizzo,a Domenico Iacopetta,a Marco Bonesi,a Vincenzo Sicari,b Teresa Maria Pellicanò,b Carmela Saturnino,c Alexia Barbarossa,a Rosa Tundis,a and Maria Stefania Sinicropia

a Dep. of Pharmacy, Health and Nutritional Sciences, University of Calabria, 87036 Rende (CS), Italy.

b Dep. of Agricultural Science, Mediterranean University of Reggio Calabria, 89123 Reggio Calabria, Italy.

c Dep. of Science, University of Basilicata, 85100 Potenza, Italy.


Several plants are considered a big reservoir of natural chemicals, many of them have been used as food for several years, without the knowledge of their benefits on human health. Recently, their extracts showed interesting in vitro anti-cancer properties, but only few have been used for treatment of these diseases.

Given the importance of this research field, the present study aimed to determine the chemical composition of the methanol extract of Anchusa azurea Mill. (Boraginaceae) aerial parts and its biological activity as antioxidant and antitumor agent against four tumor cell lines (MCF-7, MDA-MB-231, RKO, R2C). The obtained data showed that the more powerful antitumor activity was against the human colorectal RKO cells, highly aggressive and metastatic, with very low toxicity on non tumoral cells. The results have highlighted that the antitumor properties are due to the ability to induce the programmed cancer cell death through interference with the cytoskeleton dynamics. The phytochemical profile have evidenced the presence of different compounds with a good antioxidant activity, assessed by using different assays (β-carotene bleaching, ABTS, DPPH and FRAP). Furthermore, A. azurea extract protects also 3T3-L1 mouse cells from oxidative stress induced by menadione. These results demonstrate that A. Azurea could exert benefits on human health and could be used to develop new anticancer agents.

Figure 1: Anchusa Azurea.

[1] Poma P.; Labbozzetta M.; Notarbartolo M.; Bruno M.; Maggio A.; Rosselli S.; Sajeva, M.; Zito P., PloS one 2018, 13.

[2] Aissaoui H.; Mencherini T.; Esposito T.; De Tommasi N.; Gazzerro P.; Benayache S.; Benayache F.; Mekkiou R., Natural product research 2018, 1-6.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

63


Upcoming targets in neurodegenerative diseases: a molecular recognition study. Adriana Coricello,a Giosuè Costa,a Francesca Alessandra Ambrosio,a Federico Sala,b,c Stefano Alcaro,a Daniela

Rossi,b Francesca Vasile,c Simona Collinab a Dipartimento di Scienze della Salute, Università degli Studi “Magna Græcia” di Catanzaro, Viale Europa, 88100

Catanzaro, Italy. b Dipartimento di Scienze del Farmaco, Università degli Studi di Pavia, Via Taramelli 12, 27100 Pavia, Italy.

c Dipartimento di Chimica, Università degli Studi di Milano, Via Golgi 19, 20133 Milano, Italy.


The RNA-binding protein (RBP) HuD plays a critical role in the post-transcriptional control of gene

expression during nervous system development. This RBP promotes neurogenesis and favors recovery from

peripheral axon injury, pointing out the intimate relationship between HuD and neurodegenerative

disorders [1]. Nevertheless, HuD is still poorly investigated from a pharmacological point of view. Newly

identified small molecules able to interfere with HuD-RNA complexes may be useful tools for a better

understanding of HuD behavior and to identify new effective drugs.

In this work, the authors aimed to the detection of possible interfering compounds by attempting an

approach based on molecular recognition techniques followed by STD-NMR assays of potential hits.

The 1FXL model of the HuD-RNA complex was retrieved from the Protein Data Bank and subjected to molecular dynamics (MD) [2]. The protein’s behavior mimics a “clamp” which opens and closes over the RNA strand. This kind of movement causes transitions among different energetic states; for their purpose, the authors focused on the conformations associated with the highest and lowest energetic states [3]. Roughly 75 thousand small molecules were initially subjected to molecular docking against both the aforementioned conformations and after filters for druggability and PAINS were applied, eight compounds were selected for interaction studies in the presence of HuD using STD experiments. Although with different intensities, all compounds selected by virtual screening resulted able to interact with the protein, thus confirming the predictive potential of the in silico model. Further studies involving these compounds and their targeting potential against HuD may eventually open a window for the development of new therapeutic opportunity to counteract neurodegenerative diseases.

[1] Good PJ, Proceedings of the National Academy of Sciences. 1995; 92:4557-4561.

[2] Wang X, Tanaka Hall TM, Nature Structural Biology. 2001; 8:141-145.

[3] Manzoni L, Zucal C, Maio DD, D'Agostino VG, Thongon N, Bonomo I, Lai P, Miceli M, Baj B, Brambilla M, Cerofolini L, Elezgarai S, Biasini E, Luchinat C, Novellino E, Fragai M, Marinelli L, Provenzani A, Seneci P, Journal of Medicinal Chemistry. 2018; 61:1483-1498, 2018.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

64


New donepezil-like multi-target directed ligands for Alzheimer’s Disease based on hydroxytyrosol

Paola Costanzo,a Manuela Oliverio,a Rossella Paonessa,a Sonia Bonacci,a Mariorosario Masullo,b,c Rosaria Arconeb,c Monica Nardi,a and Antonio Procopioa

a Dipartimento di Scienze della Salute, Università degli Studi della Magna Græcia, Viale Europa, 88100 Loc. Germaneto

(CZ), Italy b Dipartimento di Scienze Motorie e del Benessere, Università di Napoli “Parthenope”, Via Medina 40, 80133 Napoli,

Italy c CEINGE, Biotecnologie Avanzate, S.C. a R.L., Via G. Salvatore 486, 80145 Napoli, Italy


From several epidemiological studies it results the lower incidence of Alzheimer’s Disease (AD) in the countries with Mediterranean diet. Recently it was also revealed that poly(phenolic) component of extra virgin olive oil, in particular hydroxytyrosol (HTy), could be neuroprotective against Aβ-induced neurotoxicity in neuroblastoma N2a cells [1]. Considering the multifactorial nature of AD and basing on our previous experience [2], donepezil modifications to develop novel Multi-Target Direct Ligands (MTDL) have been carried out. Then, we propose to combine the antioxidant/free radical scavenging activity of the Hty with the acetyl cholinesterase inhibition activity of Donepezil (Figure 1). The design, synthesis, characterization and biological tests of new donepezil derivatives with Hty are described.

Figure 1: Chemical structure of designed MTDL donepezil-like.

[1] St-Laurent-Thibault, C., Arseneault, M., Longpre, F., Ramassamy, C., Current Alzheimer Research 2011, 8, 543-551.

[2] Costanzo, P., Cariati, L., Desiderio, D., Sgammato, R., Lamberti, A., Arcone, R., Salerno, R., Nardi, M., Masullo, M.,

Oliverio. M., ACS Medicinal Chemistry Letters 2016, 7(5), 470-475.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

65


Exploring conformational variability of benzoxaborole derivatives for the development of selective carbonic anhydrase inhibitors

Emma Langella,a Katia D’Ambrosio,a Joelle Ayoub,a Jean-Yves Winum,b Claudiu T. Supuran,c Giuseppina De Simone,a and Anna Di Fiorea

a Istituto di Biostrutture e Bioimagini-CNR, Via Mezzocannone, 16, 80134 - Napoli, Italy.

b Institut des Biomolécules Max Mousseron, ENSCM, Université de Montpellier, 34093 Montpellier Cedex 5, France. c Laboratorio di Chimica Bioinorganica, Polo Scientifico, Università degli Studi di Firenze, Via della Lastruccia, 3-13,

50019 - Sesto Fiorentino (FI), Italy.


Carbonic anhydrases (CAs) are metalloenzymes, which catalyze the reversible hydration of carbon dioxide to bicarbonate ion and proton. These proteins are found in prokaryotes and eukaryotes, and are encoded by seven evolutionarily unrelated gene families [1]. Human (h) CAs are involved in several crucial physiological and/or pathological processes, thus becoming important targets for pharmaceutical research. For this reason, CA inhibitors are currently clinically used for the treatment or prevention of a multitude of diseases [1,2]. However, the main problem of the CAI based drugs was related to their poor selectivity since they are able to inhibit all or most of the hCA isozymes. Thus, the identification of selective CAIs is one of the main purpose for the development of new pharmacological agents.

Here we report the characterization of four novel compounds containing the benzoxaborole moiety in complex with hCA II isoform by using a combined structural and computational approach [3]. The benzoxaborole was recently identified as new zinc binding group able to interact with CA active site [4]. Our results reveal that the binding mode of these molecules depends on the substituent anchored to the benzoxaborole ring. Moreover, the role of specific residues for protein-inhibitor recognition is clarified by theoretical calculations of binding free energy.

[1] Supuran, C. T. and G. De Simone, Eds. (2015). Carbonic Anydrases as Biocatalysts - From Theory to Medical and Industrial Applications. Amsterdam, Elsevier B. V.

[2] Alterio, V.; Di Fiore, A.; D'Ambrosio, K.; Supuran, C.T.; De Simone, G. Chem Rev 2012, 112(8), 4421-4468.

[3] Langella, E.; D'Ambrosio, K.; D'Ascenzio, M.; Carradori, S.; Monti, S.M.; Supuran, C.T.; De Simone, G. Chemistry

2016, 22(1), 97-100.

[4] Alterio, V.; Cadoni, R.; Esposito, D.; Vullo, D.; Di Fiore, A.; Monti, S. M.; Caporale, A.; Ruvo, M.; Sechi, M.; Dumy, P.; Supuran, C. T.; De Simone, G.; Winum, J.-Y. Chem Commun (Camb) 2016, 52(80), 11983-11986.

This work was supported by the Italian MIUR, through the PRIN (Programmi di Ricerca di Rilevante Interesse Nazionale) Project 201744BN5T.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

66


The SF5 moiety as promising substituent for the design of novel D2 and D3 receptors ligands

Milica Elek,a Annika Frank,a Nemanja Djokovic,b Slavica Oljacic,b Aleksandra Zivkovic,a Katarina Nikolic,b and Holger Starka*

aInstitute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Duesseldorf, Universitaetsstr. 1, 40225

Duesseldorf, Germany bDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Belgrade University, Vojvode Stepe 450, Belgrade,

Serbia


Dopamine receptors are divided into two subclasses: D1 like receptors (D1 and D5 subtypes) and D2 like receptors (D2, D3 and D4) [1]. Based on a general pharmacophore [2] we introduced the pentafluorosulfanyl moiety (SF5-) group as an interesting pharmacological tool to investigate D2 like receptors. This moiety displays high electronegativity and lipophilicity, while being thermally stable [3] and more resistant to hydrolysis in comparison to that of other polyfuorinated moieties (e.g. CF3 or OCF3). Four novel compounds with SF5 substituent have been synthesized, in silico and in vitro tested in order to examine their affinity and selectivity towards human dopamine D2 and D3 receptor subtypes. All compounds showed high affinity in the nanomolar concentration ranges at both receptors with ST 2200 expressing highest selectivity. In

silico examination determined high values of coefficient of determination (R2) and Spearman correlation coefficient revealed good correlation between in silico parameters and experimentally obtained Ki values. These results show that pentafluorosulfanyl substituent is a highly suitable moiety for structural variations that has to be further investigated and could serve as novel substituent in numerous compound classes.

Figure 1: Binding mode of ST 2200 (green sticks) with pKi value of 8.42 at hD3 receptor

[1] Beaulieu, J.M.; Gainetdinov, R.R.,. Pharmacological Reviews 2011, 63 (1), 182-217.

[2] Hackling, A.E., Stark, H., ChemBioChem. 2002, 3 (10):946-658 (52), 4803-4815.

[3] Vida, N., Václavík, J., Beier, P., Beilstein Journal of Organic Chemistry, 2016, 12 (1), 110-111.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

67


A novel binuclear hydrazone-based Cd(II) complex is a strong pro-apoptotic inducer with significant activity against 2D and 3D pancreatic cancer stem cells

Nenad Filipović,a Snežana Bjelogrlić,b Sanja Marković,c Jovana Araškov,c Christian D. Muller,d Tamara Todorovićc

aDepartment of Chemistry and Biochemistry, University of Belgrade, Studentski trg 1, 11000 Belgrade, Serbia

b National Cancer Research Center of Serbia, Pasterova 14,11000 Belgrade, Serbia

c Chair of Inorganic Chemistry, University of Belgrade, Studentski trg 1, 11000 Belgrade, Serbia

d Institut Pluridisciplinaire Hubert Curien, UMR 7178 CNRS Université de Strasbourg, 67401 Illkirch, France


A novel binuclear Cd complex (1) with hydrazone-based ligand was prepared and characterized by spectroscopy and single crystal X-ray diffraction techniques. Complex 1 reveals a strong pro-apoptotic activity in both human, mammary adenocarcinoma cells (MCF-7) and pancreatic AsPC-1 cancer stem cells (CSCs). While apoptosis undergoes mostly caspase-independent, 1 stimulates the activation of intrinsic pathway with noteworthy down regulation of caspase-8 activity in respect to non-treated controls. Distribution of cells over mitotic division indicates that 1 caused DNA damage in both cell lines, which is confirmed in DNA interaction studies. Compared to 1, cisplatin (CDDP) does not achieve cell death in 2D cultured AsPC-1 cells, while induces different pattern of cell cycle changes and caspase activation in 2D cultured MCF-7 cells, implying that these two compounds do not share similar mechanism of action. Additionally, 1 acts as a powerful inducer of mitochondrial superoxide production with dissipated trans-membrane potential in the majority of the treated cells already after 6 h of incubation. On 3D tumors, 1 displays a superior activity against CSC model, and at 100 μM induces disintegration of spheroids within 2 days of incubation. Fluorescence spectroscopy, along with molecular docking show that compound 1 binds to the minor groove of DNA. Compound 1 binds to the human serum albumin (HSA) showing that the HSA can effectively transport and store 1 in the human body. Thus, our current study strongly supports further investigations on antitumor activity of 1 as a drug candidate for the treatment of highly resistant pancreatic cancer.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

68


Heterocyclic amides as selective inhibitors of HRV-B replication

Benedetta Fois,a Dirk Jochmans,b Johan Neyts,b Costantino Floris,c Rita Meleddu,a Simona Distinto,a Elias Maccioni,a and Filippo Cottigliaa

a Department of Life and Environmental Sciences, University of Cagliari, via Ospedale 72, 09124-Cagliari, Italy

b Department of Microbiology and Immunology, Rega Institute for Medical Research, Laboratory of Virology and

Chemotherapy, KU Leuven−University of Leuven, B-3000 Leuven, Belgium c Department of Chemical and Geological Sciences, University of Cagliari, Cittadella di Monserrato 09042- Cagliari, Italy


Human Rhinovirus (HRVs) are the most common viral infectious agents and they are considered the leading cause of mild upper respiratory illness in humans worldwide [1]. They are also associated with acute otitis media. Moreover, HRV infections have been reported to lead to worsening of chronic obstructive pulmonary disease (COPD) and cystic fibrosis. Despite the huge medical and socio-economical relevance of common cold, there are still no approved drugs for the treatment of these infections. However, in recent years, several molecules, such as pleconaril and vependavir, have been reported as promising therapeutic targets. In a previous work [2], a bioguided fractionation of the DCM extract of Bupleurum fruticosum resulted in the isolation of a phenylpropanoid (1) able to selectively inhibit the replication of HRV species A with an EC50 of 2.4 µM and cytotoxicity on HeLA cells of 20.3 µM. The Time-of-Drug Addition assay indicated that 1 behaves as a capsid binder. SAR studies showed that the 3,4-dimethoxyphenyl ring, as well as a long chain, seemed essential for the activity. Based on this evidence several derivatives of compound 1 have been synthesized by modifying both the phenylpropyl group and the aliphatic ester chain. In contrast with the natural compound, all synthetic active derivatives showed a reversal of selectivity towards the viral species B, HRV-14. Among all, some of the phenylpiperazine (2) or piperidinylpyridine (3) derivative amides, inhibited the replication of HRV-14 with EC50 values in the low micromolar range. Interestingly, these new compounds exhibited no cellular toxicity up to 100 µM concentration.

H3CO OO

OO

H3CO

N N

R

O

R2

R11 2

N N R

O

3

[1] Jacobs, E.S.; Lamson, D.M.; Walsh T.J., Clinical Microbiology Reviews 2013, 26, 135-162.

[2] Fois, B.; Bianco, G., Sonar, V.P.; Distinto, S.; Maccioni, E.; Meleddu, R.; Melis,C.; Marras,L.; Pompei, R.; Floris,C.; Caboni,P.; Cottiglia,F., Journal of Natural Products 2017, 80, 2799-2806.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

69


New complexes of platinum(II): effects on sensitive and resistant cells Mariafrancesca Hyeraci,1 Aida Nelly Garcia Argaez,1 Simona Samaritani,2 Luca Labella,2 Riccardo Bondi2 and

Lisa Dalla Via1

1. Dipartimento di Scienze del Farmaco, Università degli Studi di Padova, Via F. Marzolo 5, 35131 Padova

2. Dipartimento di Chimica e Chimica Industriale, Università degli Studi di Pisa Via G. Moruzzi, 13, 56124 Pisa

Cisplatin is a well-known chemotherapeutic agent that exerts its antitumor effect mainly via the generation of DNA lesions followed by the activation of the DNA damage response and the induction of apoptosis. It was first approved in 1978 by FDA for the treatment of testicular and bladder cancer and nowadays it is largely employed for the treatment of a wide number of cancer diseases, such as ovarian, non-small cell lung cancer, neuroblastoma and pleural mesothelioma1.

Notwithstanding the wide clinical use, cisplatin-based therapies suffer from dose-limiting side effects and the occurrence of intrinsic or acquired resistance. Cisplatin resistance is a multifactorial event that involves reduced intracellular uptake, increased intracellular repair of DNA damage, increased deactivation of platinum species through glutathione, metallothioneines and other cytoplasmic “scavengers” with nucleophilic properties, enhanced drug efflux and the failure of apoptotic pathways. The high incidence of chemoresistance constitutes the main limitation to the therapeutic success of cisplatin and as a consequence the search of new platinum complexes able to improve anticancer treatment outcome is still an important task among researchers.2,3

In this connection, the antiproliferative activity and the main mechanisms of action of several new complexes of platinum(II) has been investigated in comparison with cisplatin on different human tumor cell lines such as: HeLa (cervix adenocarcinoma), MSTO-211H (bifasic mesothelioma), and two well-characterized tumor cell line pairs: A2780 (wild type cisplatin-sensitive ovarian cancer) and A2780cis (cisplatin-resistant ovarian cancer). Interestingly the obtained results highlighted for some new complexes a significant antiproliferative effect along with the ability to overcome resistance.

On the bases of these results for the most interesting complexes we investigated further the biological profile with the aim to explore the intracellular target(s) involved in such ability. In particular, in order to compare the mechanism of action, being DNA the main target responsible for cisplatin cytotoxicity, we studied the interaction with the macromolecule by spectroscopic and electrophoretic techniques. The binding ability to the macromolecule and cell uptake were determined by ICP-AES. Furthermore, cytofluorimetric analysis on whole cells were performed to evaluate the impairment of intracellular pathways (cell cycle phases) or organelles (mitochondria).

The obtained results could help the development of strategies to predict and affect platinum-drug sensitivity and hence the therapeutic outcome of cisplatin-based chemotherapy.

[1] AIFA (Agenzia Italiana del Farmaco)

[2] Johnstone T.C., Suntharalingam K., Lippard S.J. Chemical Reviews 2016, 116 (5), 3436-3486

[3] Kelland L. Nature Reviews Cancer 2007, 8 (7), 573-584.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

70


Design, synthesis and biological evaluation of pyrazine derivatives Martin Juhás, Jan Zitko and Martin Doležal

Department of Pharmaceutical Chemistry and Pharmaceutical Analysis, Charles University, Faculty of Pharmacy in Hradec Králové, Akademika Heyrovského 1203/8, 500 05 Hradec Králové, Czech Republic


This research project is focused on design, synthesis and biological evaluation of new potential antimicrobial drugs of general structure shown in Figure 1A combining pyrazinamide (PZA) with selected amino acids. These structures were chosen according to our in silico screening followed by docking studies using one of the essential enzymes in clinically important bacteria including Mycobacterium tuberculosis,

the alanine racemase (Alr). Representative results from the docking studies presented in Figure 1B show two strong interactions common for our structure and alanyl-5'-pyridoxal-phosphate (PLP-Ala), a natural intermediate of the Alr indicating a possibility of competitive inhibition of the studied enzyme by our proposed structures.

A

N

OH

NH

P

O

OOH

OH

OHO

PLP-Ala

NHR3

OO

N

N

R1

PZA derivatives

O

R2 R2 = Me, Et

B

Figure 1: A: Comparison of the structure between synthesized PZA derivatives and alanyl-PLP (PLP-Ala). B: Pose of serine derivatized PZA docked to Alr compared with position of PLP-Ala.

Tested substances were synthesized from pyrazinoic acid activated using carbonyldiimidazole (CDI) and methyl or ethyl esters of the selected amino acids. Purified substances were characterized using NMR, IR and MS experiments and tested on a variety of (myco)bacterial strains including M. tuberculosis, M. avium, Staphylococcus aureus, Pseudomonas aeruginosa, fungi e.g. Candida albicans, Aspergillus flavus and others. The yields of the reactions were highly dependent on the used amino acid ranging from 10 to 95%. For more detailed results please see the presented poster.

By focusing on the Alr shared by many bacterial species we aim to find substances with inhibitory effect on several clinically important pathogens and thus help overcoming the growing antimicrobial resistance.

This work was supported by the Czech Science Foundation project No. 17-27514Y project SVV 260 401 and

Charles University Grant Agency.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

71


Conjugates of tuftsin-based peptide carriers and phenolic antitubercular molecules

Martin Krátký,a Zsuzsa Baranyai,b Szilvia Bősze,b and Jarmila Vinšováa a Department of Organic and Bioorganic Chemistry, Faculty of Pharmacy in Hradec Králové, Charles University,

Akademika Heyrovského 1203, 500 05 Hradec Králové, Czech Republic b MTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter Sétány 1/A, P.O. Box 32, 1518 Budapest 112,

Hungary


The global spread of tuberculosis (TB) especially drug-resistant Mycobacterium tubercu-losis (Mtb.) justify an intensive research on novel anti-TB drugs. In addition to novel drugs, drug delivery systems have been employed for reduction of unfavourable proper-ties, e.g., poor bioavailability, selectivity. They are also useful in targeted delivery [1].

We chose tuftsin-like peptides as carriers for anti-TB phenolic molecules (salicylanilides, disinfectant triclosan). Non-toxic tuftsin analogues stimulates several cells of immune system, target macrophages, increase cellular uptake, intracellular anti-TB activity and reduce toxicity. Additionally, they improve the solubility of lipophilic small molecules [2].

Salicylanilides and triclosan exhibited anti-TB activity including drug-resistant strains; however, they are cytotoxic considerably and their intracellular activity is limited [2,3]. To overcome these obstacles, we intended to couple them with tuftsin carriers.

Tuftsin-based peptide carriers ([TKPKG]n) were obtained using solid-phase synthesis (Fmoc/tBu strategy) and modified at N-terminus and/or lysine ε-amino group by various substituents (acyls, fluorescent labels, spacers). Salicylanilides and triclosan were converted to esters/carbamates to introduce a convenient functional group for coupling with peptides (formyl group, ω-chloroalkyl). These esters/carbamates share an enhanced anti-TB activity and lower toxicity. Follow-up conjugation was successful, e.g., oxime bond formation in the case of formyl-substituted derivatives. Surprisingly, both anti-TB activity and cytotoxicity for mammalian cells were identical for parent phenols and conjugates. Then, we confirmed a quick hydrolysis of ester/carbamate bond in the conjugates, i.e., these peptide-drug conjugates are not stable under conditions of biological evaluation. Thus, ester/carbamate bond is inapplicable for this scaffold.

This work was supported by the Czech Science Foundation project No. 17-27514Y and by the project EFSA-CDN (No.

CZ.02.1.01/0.0/0.0/16_019/0000841) co-funded by ERDF.

[1] Tiwari, G.; Tiwari, R.; Sriwastawa, B.; Bhati, L.; Pandey, S.; Pandey, P.; Bannerjee, S.K., International Journal of

Pharmaceutical Investigation 2012, 2 (1), 2-11.

[2] Baranyai, Z.; Krátký, M.; Vosátka, R.; Szabó, N.; Senoner, Z.; Dávid, S.; Vinšová, J.; Bősze, S., European Journal of Medicinal Chemistry 2017, 133, 152-173.

[3] Vosátka, R.; Krátký, M.; Vinšová, J., European Journal of Pharmaceutical Sciences 2018, 114, 318-331.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

72


The CD98hc oncoprotein as a target of novel anticancer therapeutic approaches Delia Lanzillotta,a Enrico Iaccino,a Anna Artese,b Selena Mimmi,a Isabella Romeo,b Sabrina D’Agostino,a

Vincenzo Dattilo,b Giosuè Costa,b Francesca Procopio,a Carolina Brescia,a Eugenio Gaudio,c Stefano Alcaro,b Francesco Trapassoa

aDepartment of Experimental and Clinical Medicine,

bDepartments of Health’s science, University "Magna Græcia" di Catanzaro,Viale Europa, Località Germaneto, 88100,

Catanzaro, Italy; cLymphoma and Genomics Research Program, IOR Institute of Oncology Research, Bellinzona, Switzerland


Our previous study was focused on PTPRJ, a tyrosine phosphatase with tumor suppressor activity. In order to shed light about PTPRJ, we have obtained, through a proteomic-based approach, a list of potential PTPRJ-interacting proteins. Among these possible candidates, we focused on CD98hc (SLC3A2, 4F2hc), the heavy chain of a transmembrane amino acid transporter overexpressed in several cancers [1]. Statistical analysis has demonstrated that high expression of CD98hc is associated with poor prognosis in lung cancer patients. CD98hc is linked to light chains (LATs, xCT) by disulfide bridge, polar and hydrophobic interaction[2]. The light chain confers substrate specificity and ERK, AKT, FAK and mTor pathways are involved in CD98hc-Lats/xCT downstream signals. Besides these functions, CD98hc is a co-receptor of β integrins and is implicated in cell proliferation, migration and invasion [3].

We performed a phage-display library screening to identify new potential antagonist peptides and in silico screening of chemical compounds to CD98hc. Interestingly, both types of compounds were able to reduce cell proliferation of A549 human lung cancer cells. These preliminary findings strongly encourage to a deeper characterization of these candidate anticancer molecules to develop potentially new drugs to be used in a combinatorial approach for the treatment of cancer patients.

Figure 1:

[1] D’Agostino et al. Oncotarget 2018, 9(34), 23334-23348.

[2] Yan, R. et al. Nature 2019, 568(7750), 127-130.

[3] Nguyen et al. J Clin Invest 2011, 121(5) 1733-47

BOOK of ABSTRACTS

MedChem2019




-15th

2019

73


Discovery of pyrrolo[2,3-b]pyridine nucleoside analogues as anti-

Trypanosomacruzi agents

Cai Lin,a,x Fabian Hulpia,a,x

Kristof Van Hecke,b Louis Maes,c

Guy Caljon,c Maria de Nazaré C. Soeiro,cand

Serge Van Calenbergha,* aLaboratory for Medicinal Chemistry (Campus Heymans), Ghent University, Ottergemsesteenweg 460, B-9000, Gent, Belgium.

bXStruct, Department of Chemistry, Ghent University, Krijgslaan 281 S3, B-9000, Gent, Belgium.

cLaboratory of Microbiology, Parasitology and Hygiene, University of Antwerp, Universiteitsplein 1 (S7), B-2610, Wilrijk, Belgium.

dLaboratório de Biologia Celular, Instituto Oswaldo Cruz (FIOCRUZ), Fundação Oswaldo Cruz, Rio de Janeiro, Avenida Brasil 4365,

Manguinhos, RJ, Brazil.


O

HO

HO OH

N

N

R2

R1

Chagas diseaseis a neglected tropical disease caused by Trypanosomacruzi, which is primarily transmitted via the infected triatomine vector [1]. Currently, two drugs, benznidazole and nifurtimox are available for the treatment of Chagas disease but these suffer from limited efficacy and serious side effect [2]. Since T.cruzi relies on the salvage of host purines instead of generating purine de novo [3], purine-nucleoside analogs are considered promising candidates for identifying hits against T. cruzi [4].Since the tubercidin (7-deazaadenosine) shows in vitro activity against T.cruzi [5], we decided to further explore analogues of this natural antibiotic. This presentation will focus on 1,7-dideazapurine nucleoside analogues. The 1,7-dideazapurine nucleoside was synthesized under Vorbrüggen conditions, and modification at C-6 and C-7

position was accomplished via various palladium-catalyzed coupling reactions. The substitution pattern at

C-6 and C-7 was optimized based on the in vitro activity. This led to the discovery of a 7-iodo-1,7-

dideazapurine analogue with subnanomolar anti-T.cruzi activity, clearly surpassing that of the approved

drug benznidazole.

[1] Perez-Molina, J. A.; Molina, I.,Lancet 2018, 391(10115), 82−94.

[2] Bermudez, J.; Davies, C.; Simonazzi, A.; Real, J. P.; Palma, S., Acta Trop.2016, 156,1−16.

[3] Berens, R. L.; Marr, J. J.; LaFon, S. W.; Nelson, D. J., Mol. Biochem. Parasitol.1981, 3(3), 187−196.

[4] Berg, M.; Van der Veken, P.; Goeminne, A.; Haemers, A.;Augustyns, K. I., Curr. Med. Chem.2010,17(23), 2456−2481.

[5] Finley, R. W.; Cooney, D. A.; Dvorak, J. A., Mol. Biochem. Parasitol.1988, 31(2), 133−140.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

74


Design and synthesis of new potential theranostic agents targeting tumor-expressed carbonic anhydrase IX and XII

Francesca Mancuso,a Laura De Luca,a Andrea Angeli,b Claudiu T. Supuran,b and Rosaria Gittoa aDepartment CHIBIOFARAM, University of Messina, Viale Annunziata, I-98168, Messina, Italy

bDepartment NEUROFARBA, University of Florence, Via Ugo Schiff, I-50019, Sesto Fiorentino, Italy


Human carbonic anhydrases (hCAs, EC 4.2.1.1) are metalloenzymes that catalyze the reversible hydration of carbon dioxide to bicarbonate and proton. The hCA family comprises 16 different -CA isoforms which are involved in physiopathological processes [1]. Among hCAs, the membrane-associated hCA IX and XII have been implicated in tumorigenicity, cancer metastasis. It is well known that the dimeric hCA IX isoform is over-expressed in hypoxic tumours, whilst it is not abundant in normal tissue. Therefore, hCA IX can be exploited as clinical predictor. Specifically, the expression of this isoenzyme is modulated by the hypoxia-inducible factors (HIFs-1), typically associated to aggressive tumours not responsive to chemotherapy and radiotherapy.

By cooperating with trans-membrane hCA XII, the hCA IX contributes to acidification of the extracellular environment, thus promoting local invasion and metastasis. As result, there is a reduction of the effectiveness of adjuvant therapies as well as poor cancer clinical outcomes. To obtain new theranostic tools useful in cancer therapy, an attractive strategy is recently focused on the development of new highly selective molecules targeting hCA IX/XII. On this basis, we have been engaged in the design and synthesis of potent and selective hCAs inhibitors (hCAI) from synthetic and natural sources able to counteract acidification of tumour microenvironment. In details, we have identified a large series of sulfonamides-based compounds as well as coumarin-based derivatives [2-3] being hCA IX/XII inhibitors at low nanomolar concentration. Starting from these encouraging results we designed a further series of small molecules structurally related to previous synthesized compounds. Herein we report the synthesis, biological assay as well as in silico studies for this new class of potential hCA IX/XII inhibitors.

[1] Supuran, C.; Nature Rev Drug Discov , 2008, 7, 168-81.

[2] De Luca L., Eur J Med Chem, 2018, 143, 276-82.

[3] Buemi M.R., Eur J Med Chem, 2019, 163, 443-52.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

75


New strategies for the multistep synthesis of oleocanthal Stefano Mancuso, a Paola Costanzo,a Sonia Bonacci,a Monica Nardi,a Maria Luisa Di Gioia,b Manuela Oliverioa

and Antonio Procopioa a Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, viale Europa, 88100 Catanzaro (CZ),

Italy b Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, edificio polifunzionale, 87036

Arcavacata di Rende (CS), Italy


Literature describes Oleocanthal (OC) as the major phenolic compound in extra-virgin olive oil with broad

functional and health benefits through its capacity to interact with different specific disease targets, such as cancer, inflammation, and neurodegenerative and cardiovascular diseases [1]. Numerous studies demonstrated that OC inhibits inflammation in the same way as ibuprofen; moreover, is substantially more potent on equimolar concentrations [2]. The attention toward the OC’s synthesis derives from the drawback to find an effective ways to extract it. At the best of our knowledge, in literature a rapid and effective synthetic pathway has not been developed yet; the synthesis of OC shows low yields with a huge numbers of steps. In this work, we want to overcome these disadvantages suggesting a new synthetic green strategy reducing the number of steps and improving the yield. In the Figure 1 is reported the synthetic strategy formulated by our group.

Figure 1. Strategy of synthesis of Oleocanthal.

[1] Segura-Carretero, A.; Curiel, J. A., International Journal of Molecular Sciences 2018, 19, 2899.

[2] Cicerale et al, Book Ch 19 in Olive oil - Constituents, Quality, Health Properties and Bioconversions, 2012.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

76


Toxicological profile of phenethylamine-based psychoactive drugs Daniel Martins,a Tiago Silva,a Carlos Fernandes, a Pedro Soares, a Cátia Silva, a Renata Silva,b Eva Gil-

Martins,a,b and Fernanda Borgesa

a CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Rua do Campo Alegre,

s/n, 4169-007 Porto, Portugal b UCIBIO-REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of

Porto, Rua de Jorge Viterbo Ferreira, 228, 4050-313 Porto, Portugal.

In the last years, a large number of new drugs with psychoactive properties, from different chemical classes, have appeared in the drug market worldwide. The proliferation of the so-called New Psychoactive Substances (NPS) is an emergent phenomenon that poses severe challenges to the enforcement agencies, public health systems and toxicologists, as reported by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

1 More than 450 NPS are currently being monitored by EMCDDA and some of these

drugs have also been detected as adulterants of classic illegal drugs1,2

. Phenethylamine-based new psychoactive compounds, including their highly potent hallucinogenic N-benzylphenethylamine derivatives, have been detected circulating worldwide and admitted to be related with several cases of severe intoxication.

3 N-Benzylphenethylamine derivatives have been developed as highly potent 5-HT2A agonists

and their toxicity hasn’t been clarified. Whilst the most classic illicit drugs (e.g. amphetamines, opiates) display well-established toxicological profiles, the literature regarding these NPS derivatives at this moment is scarse and limited to case studies of hospitals and poison centers.

4

Therefore, the aim of this project has been focused on the synthesis of selected phenethylamine and N-benzylphenethylamine derivatives and on the evaluation of their in vitro cytotoxicity. For that purpose, SH-SY5Y cells were exposed to the phenethylamine derivatives for different time-points and their cytotoxicity evaluated by the neutral red (NR) uptake and resazurin reduction assays

5. With the obtained data,

concentration-response curves were fitted and the EC50 values (concentration that elicits 50% cell death) were estimated for each compound. Values of log D at pH=7,4 were determined through cromathographic hidrophobicity index (CHI) data obtained by HPLC. The results obtained so far will be presented in this communication.

This project was supported by FEDER/COMPETE POCI-01-0145-FEDER-028397 and Norte-01-0145-FEDER-000028.

Daniel Martins was supported by a PhD fellowship (PD/BD/135122/2017) from The Foundation for Science and Technology (FCT, Portugal).

[1] EMCDDA, New psychoactive substances in Europe. An update from the EU Early Warning System (March 2015), in

Publication Office of the European Union, EMCDDA, Editor. 2015: Luxembourg. [2] Martins, D., et al., The detection and

prevention of unintentional consumption of DOx and 25x-NBOMe at Portugal’s Boom Festival. Human

Psychopharmacology: Clinical and Experimental, 2017. 32(3), e2608 [3] Suzuki, J., et al., Toxicities Associated With

NBOMe Ingestion—A Novel Class of Potent Hallucinogens: A Review of the Literature. Psychosomatics, 2015. 56(2): p.

129-139. [4] Halberstadt, A.L., Pharmacology and Toxicology of N-Benzylphenethylamine (“NBOMe”) Hallucinogens, in

Neuropharmacology of New Psychoactive Substances (NPS): The Science Behind the Headlines, M.H. Baumann, R.A.

Glennon, and J.L. Wiley, Editors. 2017, Springer International Publishing: Cham. p. 283-311.

[5] Fernandes, C., et al., Development of a PEGylated-Based Platform for Efficient Delivery of Dietary Antioxidants Across the Blood-Brain Barrier. Bioconjug Chem, 2018. 29(5): p. 1677-1689.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

77


Computational methods to identify bioactive food constituents with potential Multi-Targeting profile

Annalisa Maruca,a,b Raffaella Catalano,a, b Roberta Rocca,a,b Antonio Lupia,a,b Domenica M. Corigliano,a

Federica Moraca,a,b Giosuè Costa,a,b Anna Artese,a,b Francesco Ortuso,a,b Antonio Brunetti,a and Stefano Alcaroa,b

a Dipartimento di Scienze della Salute, Università “Magna Græcia”, Viale Europa, 88100-Catanzaro, Italy



Foods are naturally rich in bioactive components that affect several biological processes in our organism. Therefore, they attract great interest from the scientific community for their health benefits or desirable physiological effects [1]. Unfortunately, their mechanisms of action are often unknown or have not been enough investigated in their complexity. Here, an in silico multi-targeted approach was carried out in order to provide a molecular comprehension of the main interactions involving ligand/multi-target recognition in order to identify potential polypharmacological food bioactive compounds, thus improving the knowledge about functional foods and nutraceuticals. Firstly, a chemical database of compounds derived from different healthy foods was collected. The food database was virtually screened against macromolecular targets involved in metabolic, neurodegenerative and inflammatory diseases (Figure 1). The compounds endowed with best theoretical affinity were subjected to Molecular Dynamic simulations, in order to evaluate the target-ligand stability. The most promising hits with a multi-target profile are under biological evaluation.

Figure 1: Database building and virtual screening of natural products.

[1] Hardy, G. Nutraceuticals and functional foods: introduction and meaning. Nutrition 2000, 16(7-8), 688-689.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

78


Identification of potent and selective MAO-B inhibitors Rita Meleddu,a Simona Distinto,a Francesca Pintus,b Antonella Fais,b Benedetta Era,b Filippo Cottiglia,a

Benedetta Fois,a Serenella Deplano,a and Elias Maccionia

Department of Life and Environmental Sciences, University of Cagliari, aVia Ospedale 72, 09124-Cagliari, Italy

bCittadella Universitaria, 09042 Monserrato, Italy


Mono-amine oxidases are flavin adenine dinucleotide dependent enzymes (FAD-AO) located in the outer mitochondrial membrane of glia, neurons and many other mammalian cells. Two isoforms, MAO-A and MAO-B, have been isolated, differing from central nervous system (CNS) location, substrate specificity and sensitivity to inhibitors. Mono-amine oxidase B enzyme plays a key role in neurodegenerative disorders.1-7 Pursuing on our investigation on new scaffolds for the inhibition of MAO-B isozyme, we have synthesised and evaluated a small library of 3,5-Diaryl-4,5-dihydroisoxazoles. Most of the compounds exhibited selective inhibitory activity towards the B isoform of MAO in the nanomolar concentration range. The best performing compound was further investigated to elucidate its mechanism of action and its racemic mixture will be separated and single enantiomers inhibitory activity evaluated. Noteworthy, none of the synthesised compounds exhibited significant activity towards MAO-A. Overall, these data support our previous findings on 3,5-diaryl-4,5-dihydroisoxazoles and related compounds as promising scaffolds for the design of neuroprotective agents.

1. Biosa A, Arduini I, Soriano ME, Giorgio V, Bernardi P, Bisaglia M, Bubacco L, Dopamine Oxidation Products as Mitochondrial Endotoxins, a Potential Molecular Mechanism for Preferential Neurodegeneration in Parkinson’s Disease. ACS Chemical Neuroscience 2018; 9 (11): 2849-2858.

2. Bisaglia M, Filograna R, Beltramini M, Bubacco L, Are dopamine derivatives implicated in the pathogenesis of Parkinson's disease? Ageing Research Reviews 2014; 13: 107-114.

3. Bisaglia M, Tosatto L, Munari F, Tessari I, de Laureto PP, Mammi S, Bubacco L, Dopamine quinones interact with α-synuclein to form unstructured adducts. Biochemical and Biophysical Research Communications 2010; 394 (2): 424-428.

4. Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C, Savas JN, Kiskinis E, Zhuang X, Krüger R, Surmeier DJ, Krainc D, Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson’s disease. Science 2017; 357 (6357): 1255.

5. Jha SK, Jha NK, Kumar D, Ambasta RK, Kumar P, Linking mitochondrial dysfunction, metabolic syndrome and stress signaling in Neurodegeneration. Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease 2017; 1863 (5): 1132-1146.

6. Kang SS, Ahn EH, Zhang Z, Liu X, Manfredsson FP, Sandoval IM, Dhakal S, Iuvone PM, Cao X, Ye K, α-Synuclein stimulation of monoamine oxidase-B and legumain protease mediates the pathology of Parkinson's disease. EMBO J. 2018; 37 (12): n/a.

7. Plotegher N, Bubacco L, Lysines, Achilles’ heel in alpha-synuclein conversion to a deadly neuronal endotoxin. Ageing Research Reviews 2016; 26: 62-71.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

79


Design, synthesis and biological evaluation of Exemestane derivatives as potent inhibitors of Aromatase

Federica Moraca,a,b,c Giosuè Costa,a,b Anna Caterina Procopio,a Antonio Lupia,a,b Elisiário J. Tavares da Silva,d Fernanda M.F. Roleira,d and Stefano Alcaroa,b

a Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, viale Europa, 88100-Catanzaro, Italy.

b Net4Science Academic Spin-Off , Università "Magna Græcia", "S. Venuta", Catanzaro , Italy.

c Department of Pharmacy, University “Federico II” of Naples, via D. Montesano 49, 80131-Naples, Italy.

d Laboratory of Pharmaceutical Chemistry, Faculty of Pharmacy , University of Coimbra , 3000-548 Coimbra , Portugal.


Aromatase is a member of the cytochrome P450 superfamily, responsible for a key step in the biosynthesis of estrogens, allowing the aromatization of androgens into estrogens. For this reason, it is a very valuable therapeutic target for the selective treatment of estrogen-dependent breast cancer. Among aromatase inhibitors (AIs), Exemestane is an irreversible, steroidal aromatase inactivator of type I of clinical use. X-Ray studies revealed the existence of an access channel cavity (ACC) in correspondence of the C-4 and C-6 positions of the androstenedione complexed with aromatase [1]. This led to the design of C-6 alkyl-substituted steroids in order to better anchor in the described ACC, resulting in very efficient inhibition [2]. Starting from this evidence, we have designed, synthesized and biologically tested new series of steroidal androstanes having additional C-6 or C-7 methyl, allyl or hydroxyl groups. Among them, compound 13 (Figure 1) showed a potency and affinity to aromatase similar to Exemestane. Molecular modelling studies guided by the GRID MIFs, were useful to rationalize the best inhibition potency of 13 [3].

Figure 1: Best docking pose of compound 13 in the active site of Aromatase.

[1] Ghosh, D.; Griswold, J.; Erman, M.; Pangborn, W., Nature 2009, 457, 219-223.

[2] Ghosh, D.; Lo, J.; Morton, D.; Valette, D.; Xi, J. L.; Griswold, J.; Hubbell, S.; Egbuta, C.; Jiang,

W. H.; An, J.; Davies, H. M. L. Journal of Medicinal Chemistry 2012, 55, 8464-8476.

[3] Roleira, F.M.F.; Varela, C.; Amaral, C.; Costa, S.C.; Correia-da-Silva, G.; Moraca, F.; Costa, G.; Alcaro, S.; Teixeira, N.A.A.; Tavares da Silva, E.J., Journal of Medicinal Chemistry 2019, 62 (7), 3636-3657.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

80


Synthesis of a new cross-bridged cyclam radiotracer for PET detection of PD-L1 cancer expression.

Paolo Novelli,a Rosina Paonessa,a Sonia Bonacci,b Manuela Oliverio,b Giuseppe Lucio Cascini,a and Antonio Procopiob

a Department Experimental and Clinical Medicine, Università “Magna Græcia” di Catanzaro, Viale Europa, Localitá

Germaneto, 88100 Catanzaro, Italy b Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Viale Europa, 88100-Catanzaro (CZ),

Italy


The radioisotope 64Cu has been largely studied in PET imaging and targed radiotherapy of carcer due to its intrinsic teranostic qualities and its remarkably long half-life (12.7 h). In bifunctional compounds (BFC) are well known the ability of cyclam derivatives to chelate in a stable way copper. In particular, the 64Cu-CB-TE2A complex has shown high stability, efficient complexation and a very low in vivo tranchelation[1]. In recent years, the interest in PD-L1 has been strengthened since this protein, over-expressed in many types of cancer, is involved in the escape from the immuno surveillance of cancer cells [2]. In this work, a new radiotracer for PET imaging that through an appropriate linker, combines a specific peptidic ligang for PD-L1 with an efficient copper CB-TE2A chelator, has been synthetized. The synthetic pathway allows to realize a potential selective and non-invasive radiotracer.

Figure 1: Scheme of radiotracer probe.

[1] C. Andrew Boswell et all, Bioconjugate Chem. 2008, (19), 1476–1484.

[2] Samit Chatterjee et all, Biochemical and Biophysical Research Communications 2017, (483), 258-263.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

81


3D pharmacophore modeling of DHODH as an antimalarial target using LigandScout

Domen Oblak,a Črtomir Podlipnik,a and Sharon D. Bryantb a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Večna pot 113, 1000 Ljubljana

b Inte:Ligand, Mariahilferstrasse 74B/11, 1070 Vienna, Austria


Malaria caused mainly by the Plasmodium falciparum parasite is a deadly disease that affects about 200 million people each year, of which more than half a million die. The main problem in the treatment of malaria is that the parasites develop resistance to new drugs very quickly. The goal is to suggest a solution for the development of compounds that will lead to the development of new antimalarial agents against which plasmodia would not develop resistance.

We decided to address the problem with 3D pharmacophore modeling in LigandScout software, which has an option of ligand-based and structure-based pharmacophore modeling. Structure-based takes into account only the specific interactions between the receptor and the ligand, and it results in the 3D pharmacophore, which is a set of interactions in the 3D space, necessary for binding a small organic ligand to the receptor site of the macromolecule. Ligand-based takes into account only the features of active ligands which attach to the same receptor at the same location in the same way. With the virtual screening of different databases, we obtain potential candidates that can serve as a basis for the development of a new drug.

We mainly focused on studying human and Plasmodium falciparum Dihydroorotate Dehydrogenase (DHODH) targets. DHODH is an enzyme involved in de novo biosynthesis of pyrimidines, which are essential metabolites for many biochemical processes. This enzyme catalyzes the oxidation of dihydroorotate into orotate, with the help of two bonded cofactors – FMN and Ubiquinone. With the binding of a ligand into the Ubiquinone hydrophobic pocket, we can stop the biosynthesis. In mammals, the de novo biosynthesis of pyrimidines is only one of the sources of pyrimidines, while in P. Falciparum this is the only source. This information can be exploited for the design of a new antimalarial drug.

The main results of my research are several (8) selective 3D-pharmacophore models for DHODH that are useful for data mining, lead optimization, and understanding of key features of DHODH inhibitors associated with their inhibitory effects. The models differ in the level of specificity, and with the combination of general and selective models, we can get new compounds that could serve as inhibitors of DHODH and as such be potentially active against malaria and other DHODH dependent diseases. The combination of general and selective models also provided insight into the interaction features required for binding of the ligand to the hydrophobic pocket of DHODH.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

82


Lipid lowering and antiglycaemic properties of Tacle® by in vitro and in vivo

investigation

Maria Antonietta Occhiuzzi,a Fedora Grande,a Bruno Rizzuti,b Teresa Casacchia,a Michele De Luca,a Maria Concetta Granieri,c Carmine Rocca,c Alfonsina Gattuso,c

Jessica Ceramella,a Giuseppina Ioele,a Tommaso Angelone,c Antonio Garofaloa and Giancarlo Statti.a a Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Via P. Bucci, 87036 Rende (CS), Italy b CNR-NANOTEC, Licryl-UOS Cosenza and CEMIF.Cal, Department of Physics, University of Calabria, Via P. Bucci,87036

Rende (CS), Italy c Department of Biology, Ecology and Earth Sciences, University of Calabria, Via P. Bucci, 87036 Rende (CS), Italy


Tacle® (TC), a hybrid citrus cultivar obtained from the crossbreeding of Clementine and Tarocco, is a fruit that recently gained an increasing interest due to its commercial value and several nutraceutical properties [1]. Experimental evidences indicated remarkable protective properties of TC extract against oxidative agents, consequent to its high content in polyphenols. Herein, we report a preliminary investigation of the polyphenol content of TC extracts. Naringin and hesperidin have been recognized as as the most abundant polyphenolic glycosides present into the estract. Thus these compounds would be the main responsible for the TC beneficial effects including antioxidant, lipid lowering and hypoglycemic activities, as confirmed by specific in vitro assays. The aglycones of Naringin and hesperidin, namely naringenin and hesperetin, have been docked into amylase and lipase enzyme. As a result, both compounds proved to be able to accommodate into the active site of both enzymes. Effects on anthropometric parameters have been assessed in vivo on rats. The overall results showed an enhanced nutraceutical profile of TC with respect to citrus parents, suggesting that a dietary enrichment with its extract could be useful in the management of metabolic disorders such as obesity and diabetes [2]. Furthermore, bioactive compounds could be conveniently recovered in good yield by waste of agro-food processes, implementing the nutraceutical and commercial value of such a cultivar.

[1] Rapisarda, P.; Bellomo, S.E.; Fabroni, S.; Russo, GJournal of Agricultural and Food Chemistry 2008, 56(6), 2074-2078.

[2] Casacchia, T.; Occhiuzzi M.A.; Grande F. et al.; Journal of Functional Foods 2019, 52, 370-381.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

83


Benzoic acid-derived nitrones: a new class of acetylcholinesterase inhibitors and potential neuroprotective agents

Catarina Oliveira,a Donatella Bagetta,b,c Fernando Cagide,a José Teixeira,a,d Ricardo Amorim,d Tiago Silva,a Jorge Garrido,a,e Fernando Remião,f Eugenio Uriarte,g Paulo J. Oliveira,d Stefano Alcaro,b,c Francesco

Ortuso,b,c and Fernanda Borgesa a CIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, Porto, Portugal;

b

Dipartimento di Scienze della Salute, Università "Magna Græcia" di Catanzaro, Campus Universitario "S.Venuta", Catanzaro, Italy;

c Net4Science Academic Spin-Off, Università "Magna Græcia" di Catanzaro, Catanzaro, Italy;

d CNC –

Center for Neuroscience and Cell Biology, University of Coimbra, UC-Biotech, Biocant Park, Cantanhede, Portugal; e

Department of Chemical Engineering, Superior Institute of Engineering of Porto (ISEP), IPP, Portugal; f UCIBIO-

REQUIMTE, Laboratory of Toxicology, Department of Biological Sciences, Faculty of Pharmacy, University of Porto,

Porto, Portugal; g Department of Organic Chemistry, Faculty of Pharmacy, University of Santiago Compostela, Santiago

de Compostela, Spain.


Alzheimer’s disease (AD) is a multi-factorial disease deeply associated with impaired cholinergic transmission and oxidative stress, a process that is related with a failure in the antioxidant protective system and/or an increment in reactive species production/accumulation. In this context, the discovery of new chemical entities endowed with potent and selective acetylcholinesterase (AChE) and/or butyrylcholinesterase (BChE) inhibitory activity is still a relevant subject for Alzheimer’s disease therapy. Therefore, a small library of benzoic based amide nitrones, a class of compounds known as spin traps [1], (compounds 24 to 42) was synthesized and screened toward cholinesterase enzymes (AChE and BChE). SAR studies showed that the tert-butyl moiety is the most favourable nitrone pattern, as the tert-butyl derivatives effectively inhibited AChE and none of compounds showed BChE inhibitory activity. Molecular modelling studies provided insights into the enzyme-inhibitor interactions and rationalised the experimental data. In addition, their cytotoxic and neuroprotective profile was evaluated in SH-SY5Y and in HepG2 human cell lines. The results obtained so far will be presented in this communication.

This project is supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, POCI-01-0145-FEDER-029164, and NORTE-01-0145-FEDER-000028). CO, TS (SFRH/BPD/114945/2016), CF, RA and JT grants were also supported by FCT and FEDER/COMPETE and NORTE 2020 funds.

[1] Oliveira, C.; Benfeito, S.; Fernandes, C.; Cagide, F.; Silva, T.; Borges, F., Medicinal Research Reviews 2018, 38 (4), 1159-1187.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

84


Arsenous acid-platinum(II) a new dual pharmacophore anti-cancer agent: computational insights

Angela Parise,a Tiziana Marino,a and Nino Russoa a Dipartimenti di Chimica e Tecnologie Chimiche, Università della Calabria , 87036 Arcavacata di Rende , Italy


Platinum(II)-based molecules are the most commonly used anticancer drugs in the chemotherapeutic treatment of tumors but possess serious side effects and some cancer types exhibit resistance with respect to these compounds (e.g. cisplatin). For these reasons, the research of new compounds that can bypass this limitation is in continuous development. Recently, mixed Pt(II)-As(III) systems have been synthesized and tested as potential anticancer agents. The first representative of this novel class of anti-cancer agents displays a superior activity profile relative to the parent drugs As2O3 or cisplatin in majority of cancer cell lines tested. The mechanism of action of these drugs is still unclear. Since in other platinum(II) containing drugs, hydrolysis plays an important role in the activation of the compound before it reaches DNA, we have explored the aquation process using density functional theory (DFT), focusing our attention on the arsenoplatin complex, [Pt(μ-NHC(CH3)O)2ClAs(OH)2]. As DNA is believed to be the main cellular target for Pt anticancer drugs, the metalation mechanism of DNA purine bases has been also investigated. Also for this new drug it appears that guanine is the preferred site with respect to adenine as with other platinum-containing compounds. A comparison with cisplatin is performed in order to highlight the contribution of arsenic in the anticancer activity of this new proposed anticancer agent.[1]

Moreover, recently it was shown that the arsenoplatin complex (Figure 1) acts as a unique and dual pharmacophore anticancer agent.[2] With the aim to evaluate at atomistic level, the interaction mechanism of the arsenoplatin compound with specific amino acid residues of some proteins involved in the hydrolysis of RNA and, a theoretical study at density functional theory level, has been undertaken. In this study, histidine of hen egg white lysozyme (HEWL) and methionine of RNase A have been used as target.

Figure 1: Arsenoplatin complex.

[1] Marino, T.; Parise, A; Russo, N., Physical Chemistry Chemical Physics 2017, 19 (2), 1328-1334.

[2] Miodragović, D.; Merlino, A.; Swindell, E. P.; Bogachkov, A.; Ahn, R. W.; Abuhadba, S.; Ferraro, G.; Marzo, T.; Mazar, A. P.; Messori, L.; O’Halloran, T. V., J. Am. Chem. Soc. 2019, 141 (16), 6453-6457.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

85


Molecular docking and design of novel 2, 3-aryl-thiazolidin-4-ones as potent NNRTIs inhibitors

A. Petrou,1 A. Geronikaki,1 V. Kartsev,2 R. Boga3 1 School of Pharmacy, Aristotle University of Thessaloniki, Thessaloniki, 54124, Greece

2 InterBioscreen, Moscow, Russia

3 BogaR Laboratories LLC, Suwanee, USA

This work presents and discusses the design of 16 novel 2, 3-aryl-thiazolidin-4-ones, with increased activity against human immunodeficiency virus (HIV) based on docking evaluation and PASS prediction.

HIV is the causative agent of Acquired Immunodeficiency Syndrome (AIDS), an infectious disease with increasing incidence worldwide. Non-nucleoside reverse transcriptase inhibitors or NNRTIs play an important role in the treatment of AIDS. However, despite the fact that many compounds are already being used as anti-HIV drugs, research into the development of new inhibitors continues as the virus develops resistant strains, limiting their use.

Taking into account the best features of available NNRTIs and with the aid of Molecular docking studies and PASS, it is attempted to design new compounds that will not be blocked by small mutations in the reserve transcriptase (RT) binding domain, but they will exhibit a big number of interactions with RT by enhancing their anti-HIV-activity. The designed compounds, synthesized and their activity as RT inhibitors by in vitro assay are in progress.

Fig. 1: (Left) Docked pose of compound k2 and HIV-1 Reverse Transcriptase complex; (right) 2D ligand interaction diagram for docked ligand.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

86


Synthesis and evaluation of novel antimycobacterial isoniazid analogues

Václav Pflégr,a Martin Krátký,a Sara Bruno,a,b Jiřina Stolaříková,c Szilvia Bősze,d and Jarmila Vinšováa

aDepartment of Organic and Bioorganic Chemistry, Faculty of Pharmacy, Charles University, Akademika Heyrovského

1203, 500 05 Hradec Králové, Czech Republic bDepartment of Biological, Chemical and Pharmaceutical Sciences and Technologies, Scuola delle Scienze di Base e

Applicate, Università degli Studi di Palermo, Via Archirafi 28, 90123 Palermo, Italy cLaboratory for Mycobacterial Diagnostics and Tuberculosis, Institute for Public Health in Ostrava,

Partyzánské náměstí 2633/7, 702 00 Ostrava, Czech Republic dMTA-ELTE Research Group of Peptide Chemistry, Pázmány Péter sétány 1/A, P.O. Box 32, 1518, H-1117, Budapest,

Hungary


Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is responsible for the highest mortality rates worldwide due to a single infectious agent [1]. One of the major complications of TB therapy is the increasing resistance of mycobacterial strains to conventional drugs. This is very serious problem especially for immunosuppressed (e.g. HIV co-infected) patients [2]. Anti-TB therapy intends to avoid complications and mortality, cure the individual, prevent recurrences, decrease the possible conveyance to sensitive individuals, and restrict the appearance and dissemination of strains that are drug-resistant [3]. Isoniazid (INH; pyridine-4-carbohydrazide) is one of the first-line drugs in anti-TB therapy.

We are focused on synthesis and evaluation of novel isoniazid analogues, predominantly hydrazones with various oxocarboxylic acids that are further modified on free carboxyl group by various aromatic and non-aromatic amines or phenols to yield amides and esters (via EDC coupling catalysed by 1-hydroxybenzotriazole or 4-(dimethylamino)pyridine). The hydrazone bond was also reduced in several compounds to form 1,2-disubstituted hydrazides. Another structural motive was formed by the addition of a bromine atom to the position 2 of the pyridine core.

The prepared derivatives were characterized and their in vitro antimycobacterial activity (Mtb. H37Rv, M.

avium, M. kansasii) was evaluated.

The best activity against Mtb. showed 2-(2-isonicotinoylhydrazineyl)-N-phenylpropanamides substituted by an electron-withdrawing group at anilide ring (4-OCF3, MIC ≤0.03 µM), an additional aromatic ring or a long alkyl at anilide ring and also 2-napthylamide (MIC values from ≤0.25 µM). The highest efficacy against nontuberculous mycobacteria (MIC from ≤1 µM) exhibited 2-(2-isonicotinoylhydrazineylidene)-N-(4-phenoxyphenyl)propanamide.

Importantly, the presented compounds are selective, non-toxic for mammalian cells (HepG2, MonoMac6) and several of them are comparable or significantly superior (17×or more) to parent INH. Their activity against multidrug- and extensively drug-resistant tubercular strains is currently under investigation.

This work was supported by the Czech Science Foundation project No. 17-27514Y and SVV 260 401.

[1] Bengtson, H. N.; Homolka, S.; Niemann, S.; Reis, A. J.; Silva da, P. E.; Gerasimova, Y. V.; Kolpashchikov, D. M.; Rohde, K.H., Biosensors and Bioelectronics 2017, 94, 176-183.

[2] Vosátka, R.; Krátký, M.; Vinšová, J., European Journal of Pharmaceutical Sciences 2018, 114, 318-331.

[3] Al Matar, M.; Al Mandeal, H.; Var, I.; Kayar, B.; Köksal, F., Biomedicine & Pharmacotherapy 2017, 91, 546-558.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

87

Figure 1: Adopted strategy to overcome tolcapone’s hepatotoxicity by using tolcapone-loaded nanoparticles.


De-risking tolcapone hepatotoxicity for repurposing therapy using a nanotechnological approach

Miguel Pinto,a Carlos Soares,a Carlos Fernandes,a Fernanda Borgesa

aCIQUP/Department of Chemistry and Biochemistry, Faculty of Sciences, University of Porto, 4169-007, Porto,

Portugal.


Tolcapone is an orally active catechol-O-methyltransferase (COMT) inhibitor authorized in the United States and Europe as an adjunct to levodopa and carbidopa for the treatment of Parkinson’s disease. Despite effective and potent, tolcapone has a highly hepatotoxic profile, which led to the introduction of a "black box" warning and intensive monitoring requirements during its application [1]. Recent studies reported that tolcapone is a strong candidate for the treatment of familial amyloid polyneuropathy [2] and neuroblastoma [3]. Hence, tolcapone seems a clear case of the repurposing of an old drug for new treatments, especially for those related with neuronal disorders. However, the hepatotoxic profile may be a limiting feature for its application. Recent developments in nanoscience and nanotechnology have given rise to a new generation of functional nanomaterials with controlled morphology and well-defined properties that can be part of a solution to solve several drawbacks, namely cytotoxic aspects [4]. Therefore, the aim of the project is the development of a new polymeric carrier with controlled drug release features in order to overcome the hepatotoxic issues of tolcapone (Figure 1). In that regard, tolcapone-loaded PLGA nanoparticles were synthesized after a brief optimization process using the nanoprecipitation method [5]. The data related to physicochemical, morphological and bioavailability properties of the new nanoformulations will be presented in the communication.

This project is supported by Foundation for Science and Technology (FCT) and FEDER/COMPETE (Grants UID/QUI/00081/2019, POCI-01-0145-FEDER-029164, and NORTE-01-0145-FEDER-000028). MP and CF grants were also supported by NORTE 2020 funds.

[1] Olanow, C.W.; Panel, T.A., Arch Neurol-Chicago, 2000, 57 (2), 263-267.

[2] Sant'Anna, R.; Gallego, P.; Robinson, L.Z.; Pereira-Henriques, A.; Ferreira, N.; Pinheiro, F.; Esperante, S.; Pallares, I.; Huertas, O.; Almeida, M.R.; Reixach, N.; Insa, R.; Velazquez-Campoy, A.; Reverter, D.; Reig, N.; Ventura, S., Nature Communications, 2016, 7,

10787.

[3] Maser, T., Rich, M.; Hayes, D.; Zhao, P.; Nagulapally, A. B.; Bond, J.; Sholler, G., Cancer Medicine, 2017, 6 (6), 1341-1352.

[4] Khalil, N.M.; Mainardes, R.M., Current Drug Delivery, 2009, 6 (3), 261-273.

[5] Fessi, H.; Puisieux, F.; Devissaguet, J.Ph.; Ammoury, N.; Benita, S., International Journal of Pharmaceutics, 1989, 55 (1), R1-R4.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

88


In silico identification of new aromatase inhibitors

Anna Caterina Procopio and Stefano Alcaro aDipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Viale Europa, 88060 Catanzaro, Italy


The aromatase is a microsomal enzyme, belonging to the superfamily of the cytochromes p450, which catalyzes the aromatization reaction from androgens to estrogens. An over-expression of such enzyme leads to an overproduction of estrogens, creating a favorable environment for uncontrolled tissue growth [1]. Moreover, the X-ray crystal structure of human placental aromatase complexed with breast cancer drug exemestane (figure 1) allows to perform receptor-based drug design for the identification of novel inhbitors.

Figure 1: exemestane within the binding pocket of the Aromatase.

In order to identify new aromatase inhibitors, a library of currently approved drugs in clinical practice, was downloaded from DrugBank on-line database [2]. Indeed, the drug-repurposing allows to overcome some of the most common problems for the discovery of new drugs such as toxicity and poor pharmacokinetic profile. These compounds were virtually screened by molecular docking studies. According to the binding affinity values and the interactions with known important active residues, 3 hits compounds were identified and submitted to 100 ns of molecular dynamics (MD) simulations. MD analysis confirmed that the identified compounds are promising aromatase inhibitors, which could be evaluated by enzymatic assays.

[1] Chumsri, S.; Howes, T.; Bao, T.; Sabnis, G.; Brodie, A.; Aromatase, Aromatase inhibitors, and breast Cancer , Journal of Steroid Biochemistry and Molecular Biology., 2011,125 (1-2),13-22.

[2] Wishart, D.S.; Knox, C.; Guo, A.C.; Cheng,D.; Shrivastava, S.; Tzur, D.; Gautam, B.; Hassanali, M.; DrugBank: a knowledgebase for drugs, drug action and drug targets. Nucleic Acids Research., 2008,36, D901-D906.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

89


An in vivo biologically active pyrido[2,3-d]pyrimidine as a KRAS and tyrosine kinase inhibitor for the potential treatment of lung cancer

Raimon Puig de la Bellacasa,a Roger Estrada-Tejedor,a Alberto Villanueva,b,c Javier Rivela,d José I. Borrella

aGrup de Química Farmacèutica, IQS School of Engineering, Universitat Ramon Llull, Via Augusta 390, 08017

Barcelona, Catalunya (Spain) bXenopat S.L, Business Bioincubator, Bellvitge Health Science Campus, L’Hospitalet de Llobregat, 08907 Barcelona,

Catalunya (Spain) cChemoresistance and Predictive Factors Laboratory, ProCURE, Catalan Institute of Oncology (ICO), Oncobell, IDIBELL,

L’Hospitalet de Llobregat, 08908 Barcelona, Catalunya (Spain) dPangaea Oncology, Quirón Dexeus University Hospital, Sabino Arana 5-19, 08028 Barcelona, Catalunya (Spain)


Oncogenic mutations of KRAS (Kirsten rat sarcoma viral oncogene homolog) are frequently identified in lung, colorectal and pancreatic cancers. After 30 years of intensive research, there is not yet an effective clinical drug against this target [1].

In this context, our group, with a large experience in synthesis of pyrido[2,3-d]pyrimidines (Figure 1) [2], a privileged heterocyclic scaffold able to inhibit different tyrosine kinases, has recently reached to get a compound (IQS080) with activity against KRAS. IQS080 has shown in vitro activity against different cancer cell lines and very promising in vivo results (Figure 1). In order to demonstrate the mechanism of action of IQS080, enzymatic assays and surface plasmon resonance (SPR) were performed, showing respectively, inhibition of key tyrosine kinases, such as EGFR, p-38 and ERK1/2; and KRAS interactions at GTP binding site.

Figure 1: General pyrido[2,3-d]pyrimidine scaffold and in vivo results of IQS080.

[1] Xie, C.; Li, Y.; Li, L-L.; Fan, X-X.; Wang, Y-W.; Wei, C-L.; Liu, L.; Leung, E. L-H.; Yao, X-J., Frontiers in Pharmacology 2017, 8, art. 823.

[2] (a) Puig de la Bellacasa, R.; Roué, G.; Balsas, P.; Pérez-Galán, P.; Teixidó, J.; Colomer, D.; Borrell, J.I., Eur. J. Med. Chem. 2014, 86, 664-675. (b) Camarasa, M.; Puig de la Bellacasa, R.; González, A.L.; Ondoño, R.; Estrada, R.; Franco, S.; Badia, R.; Esté, J.; Martínez, M.A.; Teixidó, J.; Clotet, B.; Borrell, J.I., Eur. J. Med. Chem. 2016, 115, 463-483.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

90


Can boron-containing compounds be considered new structural scaffolds for the treatment of Alzheimer’s disease?

Alessandra G. Ritacca,a Nino Russoa and Emilia Siciliaa a Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Arcavacata di Rende, 87036-CS, Italy


Since Alzheimer’s disease (AD) has been first described more than 100 years ago, it is now thought to affect 2% of the industrial world’s population and is the third leading cause of death in these countries [1]. Due to the complex pathogenesis of AD, there are only five drugs approved by the FDA for the treatment of AD to date [2][3]. The development of new drugs for the treatment of AD, thus, remains a challenge in the pharmaceutical community. Very recently, a novel series of boron-containing compounds has been proposed, exhibiting multifunctional activity as potential anti-AD drugs, including a significant ability to inhibit self-induced Aβ aggregation and to act as antioxidants and biometal chelators [4]. Here are presented the outcomes of a DFT computational exploration of such multifunctional activity with the aim to test whether boron-containing compounds might be used as new structural scaffolds for the treatment of AD. Computational investigation has been carried out on the members of the series considered to be the most promising candidates.

[1] Mattson, M.P., Nature 2004, 430, 631–639

[2] Pepeu, G. M.; Giovannini, G., Curr. Alzheimer Res. 2009, 6, 86

[3] Tayeb, H. O.; Yang, H. D.; Price, B. H.; Tarazi, F. I., Pharmacol. Ther. 2012, 134, 8

[4] Lu, C.-J.; Hu, J.; Wang, Z.; Xie, S.; Pan, T.; Huang, L.; Li, X, Med. Chem. Commun. 2018, 9, 1862

BOOK of ABSTRACTS

MedChem2019




-15th

2019

91


Identification of small molecules with specific interference to lncRNA activity through different computational approaches

Roberta Rocca,1,2 Nicola Amodio,2 Annalisa Maruca,1,2 Raffaella Catalano,1,2 Katia Grillone,2 Giada Juli,2 Giosuè Costa,1,2 Stefano Alcaro,1,2 Pierosandro Tagliaferri,2 Pierfrancesco Tassone2

1Net4Science Academic Spin-Off, Catanzaro, Italy

2Università “Magna Græcia” di Catanzaro, Catanzaro, Italy;

3


Long non-coding RNAs (lncRNAs) are a class of non-protein coding RNA molecules with more than 200 nucleotides in length, whose aberrant expression has proven crucial in cancer pathogenesis (1). Particular interest has been recently given to the three-dimensional (3D) conformation of RNAs, since it offers potential targeting sites for small molecules (SMs) (2). In this perspective, we applied different computational approaches to discover new SMs with specific interference to oncogenic lncRNAs, in order to antagonize their activity. In detail, two different strategies have been taken into account. The first approach allowed to identify compounds directly interacting with lncRNAs, through the study of their sequences and 3D structures, while the second one has been addressed to identify SMs able to prevent the binding between lncRNAs and their effector proteins, specifically targeting RNA-binding domains. Currently, two lncRNA, namely TERRA and MALAT1(3), and the Polycomb Repressive Complex 2 (PRC2) (4), one of its binding partners, are under deeply investigation in our lab, by means of different computational approaches, including docking, molecular dynamics and metadynamics simulation.

Figure 1. LncRNAs (MALAT1 and TERRA) and its interacting protein PRC2. Docking and dynamics simulations will be exploited for the selection of new potential anti-cancer SMs, inhibiting directly the lncRNA and/or indirectly its enzyme. Further methadynamics studies will define their binding mode.

Acknowledgment: Italian Association for Cancer Research (AIRC): “Small molecule-based targeting of lncRNAs 3D

structure: a translational platform for the treatment of multiple myeloma” (no. 21588, pi Tassone, 2018).

1. Cheetham, S. W., Gruhl, F., Mattick, J. S., & Dinger, M. E. Long noncoding RNAs and the genetics of cancer. British journal

of cancer, 2013, 108, 2419.

2. Rocca, R., Moraca, F., Costa, G., Nadai, M., Scalabrin, M., Talarico, C., Distinto, S., Maccioni, E., Ortuso, F., Artese, A., Alcaro, S., Richter, S. Identification of G-quadruplex DNA/RNA binders: structure-based virtual screening and biophysical characterization. Biochimica et Biophysica Acta (BBA)-General Subjects, 2017, 1861(5), 1329-1340.

3. Brown, J. A., Bulkley, D., Wang, J., Valenstein, M. L., Yario, T. A., Steitz, T. A., & Steitz, J. A. Structural insights into the stabilization of MALAT1 noncoding RNA by a bipartite triple helix. Nature structural & molecular biology, 2014, 21(7), 633.

4. Justin, N., Zhang, Y., Tarricone, C., Martin, S. R., Chen, S., Underwood, E., & Wilson, J. R. Structural basis of oncogenic histone H3K27M inhibition of human polycomb repressive complex 2. Nature communications, 2016, 7, 11316.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

92

Paul Erhlich & MuTaLig Poster Communications 40 (PC_40)

Mechanistic insights of hydrolytic activity into a de novo functional protein

framework.

Isabella Romeo, Mario Prejanò, Tiziana Marino and Nino Russo

Dipartimento di Chimica e Tecnologie Chimiche, Università della Calabria, Rende, 87036 Italy


De novo protein design represents an attractive challenge in which both structure and function are built from scratch. Indeed, these enzyme-like catalysts could play a pivotal role for manipulating and obtaining small molecules with prospective applications in medicine and industrial biotechnology [1]. Recently, this goal was achieved with the installation of the esterase activity into an entirely de novo designed homo-heptameric peptide assembly (CC-Hept) [2]. The reaction mechanism of CC-Hept, obtained by engineering the functional catalytic triad (Cys-His-Glu) into a channel, is proposed on the basis of a combined molecular dynamics (MD) and hybrid quantum mechanics/molecular mechanics (QM/MM) investigation (Figure 1). The preliminary MD simulations have been performed on both unbound and bound to the model substrate (p-nitrophenyl acetate) protein, thus supporting the stability of de novo protein architecture. Two reaction pathways have been deeply analyzed at QM/MM level evidencing the rate determining step in agreement with the observed kinetics evidences. The roles of water molecules and of Cys-His-Glu catalytic triad have been highlighted at atomistic level. Our results should be useful for future developments of more selective and efficient engineered enzymes.

Figure 1: (A) Crystal structure of CC-Hept (B) pNPA-bound protein (C) Extrapolated QM/MM model from MDs. (D)

Focus on QM region residues involved in the proposed catalytic mechanisms.

[1] Nanda, V.; Koder, R.L., Nature Chemistry 2010, 2, 15-24.

[2] Burton, A.J.; Thomson, A.R.; Dawson, W.D.; Brady, R.L.; Woolfson, D.N., Nature Chemistry 2016, 8, 837-844.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

93


Synthesis of furochromone derivatives with potential anticancer activity Lisa Sequeira, aRita Meleddu,a and Elias Maccionia

aDepartment of Life and Environmental Sciences, University of Cagliari,Via Ospedale 72, 09124-Cagliari, Italy


Carbonic anhydrases (CAs) are a class of metallo-enzymes that catalyze the reversible hydration of carbon dioxide into bicarbonate and a proton and are widely distributed in all living organisms [1,2]. These enzymes are involved in numerous physiological processes such as ion transport, regulation of pH, bone resorption, and secretion of gastric, cerebrospinal fluid and pancreatic juice [3]. In mammals CAs have 16 different isoforms and multiple ones implicated in a range of diseases, including cancer [2]. In particular, the trans-membrane CAs IX and XII are key pH regulators that create a differential pH microenvironment within solid tumors and allow for tumor cell survival under stressful conditions [2]. For this reason CAs became an increasing interest to researchers as drug targets, and, as a result, a number of CAs inhibitors have been designed [1]. Furochromones are very interesting O-heterocycles which are present in nature and show a wide range of biological activities, such as anti-HIV activity, aromatase inhibitory effect and anticancer potency [4].

Accordingly, our project is focused in the development of CAs inhibitors based on the furochromone scaffold. To achieve this goal several 8-oxo-3-phenyl-8H-furo[2,3-g]chromene-7-carboxylic acid derivatives (Figure 1) are being synthesized. The results obtained so far will be presented in this communication.

OO

R3 OR1

R2 Figure 1: General structure of the compounds proposed for synthesis.

Acknowledgements:

Lisa Sequeira grant was supported by Univerità degli Studi di Cagliari (funds from the Italian Ministry of Education, University and Reasearch).

[1]Meleddu, R., et al., Tuning the Dual Inhibition of Carbonic Anhydrase and Cyclooxygenase by Dihydrothiazole Benzensulfonamides. Acs Medicinal Chemistry Letters, 2018. 9(10): p. 1045-1050.

[2]Singh, S., et al., Cancer Drug Development of Carbonic Anhydrase Inhibitors beyond the Active Site. Molecules, 2018. 23(5).

[3]Bianco, G., et al., N-Acylbenzenesulfonamide Dihydro-1,3,4-oxadiazole Hybrids: Seeking Selectivity toward Carbonic Anhydrase Isoforms. Acs Medicinal Chemistry Letters, 2017. 8(8): p. 792-796.

[4] Abu-Hashem A. A., et al, Synthesis, reactions and biological activities of furochromones: A review. Eur J Med Chem, 2015. 90: p. 663-665.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

94


Computational conception and chemical synthesis of dual BTK-TCL1 inhibitors Simona Sestito,1 Roberta Rocca,2 Giosuè Costa,2 Antonio Lupia,2 Francesco Trapasso,2 Eugenio Gaudio,3

Stefano Alcaro,2 Simona Rapposelli1

1 University of Pisa, Pisa, Italy;

2 Università “Magna Græcia” di Catanzaro, Italy; 3 Università della Svizzera

italiana, Institute of Oncology Research, Bellinzona, Switzerland.


Introduction. The Bruton tyrosine kinase (BTK) inhibitor Ibrutinib has been approved by the FDA for the treatment of many lymphomas and chronic lymphocytic leukemia (CLL). Ibrutinib is used both as single agent or combined to Rituximab (anti-CD20 mAb) and to the traditional chemotherapy (e.g. CHOP) for the treatment of lymphoma’s patients. Despite the improvements, still too many patients die for their diseases and more medicine are needed. In respect of this consideration, we designed and synthesized a list of novel BTK inhibitors having the capability to also hit, at the in silico level, another important and so far “undruggable” target, the T-cell leukemia/lymphoma 1 (TCL1) protein [1,2].

Results. The initial proposed hit compound, namely “12R”, and its synthesized derivatives (ES1-10) have been in silico

evaluated for their binding energy versus the two putative targets, BTK and TCL1. Interestingly, some optimized compounds showed higher affinity versus BTK than ibrutinib. The affinity versus TCL1 could not be compared with any competitors, since there are not available TCL1 inhibitors. The most interesting compound ES8 showed anti-proliferative activity (IC50 ≤ 10 μM) in a small panel of six lymphoma cell lines.

Figure 1. The 2D structure of the most interesting compound ES8 and ITS best complexes with BTK and TCL1, respectively.

1. Paduano, F.; Gaudio, E.; Mensah, A.A.; Pinton, S.; Bertoni, F.; Trapasso, F. T-cell leukemia/lymphoma 1 (tcl1): An oncogene regulating multiple signaling pathways. Frontiers in oncology 2018, 8, 317-317.

2. Bresin, A.; D'Abundo, L.; Narducci, M.G.; Fiorenza, M.T.; Croce, C.M.; Negrini, M.; Russo, G. Tcl1 transgenic mouse model as a tool for the study of therapeutic targets and microenvironment in human b-cell chronic lymphocytic leukemia. Cell Death &Amp; Disease 2016, 7, e2071.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

95


New route for the synthesis of 1-(arylimidazolin-2-yl)-3-arylureas D. Straszaka and D. Matosiuka

a Department of Synthesis and Technology of Drugs, Medical University in Lublin, Chodźki 4a Street, 20-093 Lublin,

Poland


Chronic pain is one of the most common symptoms of many diseases, and in the era of increased morbidity and prolonged median survival of patients is becoming a growing clinical problem. Therapy of these patients is based mainly on non-steroidal anti-inflammatory drugs, but unfortunately their effectiveness in combating the severe or chronic pain is limited.

Much stronger analgesic effect can be observed with the use of opiates, however, a number of sides effects limits their use mainly to the group of terminal patients. Among the adverse effects of opioid therapy are the developing tolerance, psychophysical addiction and depression of the respiratory center.

Series of 1-(arylimidazolin-2-yl)-3-arylureas synthesized by Matosiuk and co-authors showed analgesic properties that were confirmed in in vitro and behavioral tests[1]. The main aim of our work was to create a new method of synthesis of 1-aryl-2-iminoimidazolidine derivatives containing urea moiety by using simple and commercially available substrates.

In a multi-step reaction, the primary arylamines were treated with triphosgene in the presence of

triethylamine to form arylisocyanates. Further, nucleophilic substitution of obtained products with appropriate 1-aryl-2-iminoimidazolines-2 led to formation of 1-(arylimidazolin-2-yl)-3-arylureas. The synthesis was carried out in dry toluene with two scales of temperatures: 250C and 1000C with good yelds. The final products had been purified from byproducts by applying chromatographic techniques (Fig. 1). As last, the title compounds were fully characterized by using spectral methods (API-MS, 1H NMR) and elemental analysis.

N

NH

NNH

O

R2

R1

R1= H, 2-CH3, 3-CH3, 4-CH3, 2-Cl, 3-Cl, 4-Cl; R

2= H, CH3

Fig. 1

All obtained compounds are currently under biological evaluation as a potential active agents for opioid receptors.

[1]

Matosiuk, D.; Fidecka, S.; Antkiewicz-Michaluk, L.; Dybała, I.; Kozioł, A.E., European Journal of Medicinal Chemistry 2001, 36, 783-797.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

96


Combined ultrasound/microwave chemocatalytic method for selective conversion

of cellulose into lactic acid

Sofia Tallarico,a Paola Costanzo,a Sonia Bonacci,a Monica Nardi,a Maria Luisa Di Gioia,b Antonio Procopioa and Manuela Oliverioa

a Dipartimento di Scienze della Salute, Università “Magna Græcia” di Catanzaro, Viale Europa, 88100-Catanzaro (CZ),

Italy b Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Edificio Polifunzionale, 87036-

Arcavacata di Rende (CS), Italy


Lactic acid (LA) is a chiral α-hydroxy acid traditionally used in food industry as acidulant, preservative and emulgator [1]. Next to these classical applications, LA has the potential to become a precursor for the synthesis of α-amino acids, opening to the production of proteins from agricultural wastes via chemical routes in the future [2].

In this work, we present an alternative US/MW combined chemocatalytic method to realize the selective hydrothermal conversion of cellulose into LA, under mild reaction conditions in presence of ErCl3 grafted on MCM-41 silica surface. Preliminary data shows very good yields and high selectivity for the sustainable scale-up synthesis of LA either for biomass carbohydrates or for cellulose. Thanks to the effect of US on the de-crystallinization of cellulose, its MW assisted conversion into LA was possible at temperature and pressure under the water subcritical conditions, increasing operational safety and improving the catalyst recovery and reuse.

OOOO

OH

OH

HO HO

OH

OH

n

OH

O

OH

lactic acid

O

O

OH

levulinic acid

O

O OH

5-hydroxymethylfurfural

OO

furfural

ErIII-MCM-41

US/MW

200°C

H2O

Cellulose/ Biomass carbohydrates

Figure 1: Catalytic hydrothermal conversion of cellulose and biomass carbohydrates.

[1] Dusselier, M.; Van Wouwe, P.; Dewaele, A.; Makshina, E.; Sels, B. F.. Lactic acid as a platform chemical in the biobased economy: the role of chemocatalysis. Energy Environ. Sci., 2013, 6, 1415-14421

[2] Deng, W.; Wang, Y.; Zhang, S.; Gupta, K.M.; Hulsey, M.J.; Asakura, H.; Liu, L.; Han, Y.; Karp, E.M.; Beckham, G.T.; Dyson, P.J.; Jiang, J.; Tanaka, T.; Wang, Y.. Catalytic amino acid production from biomass-derived intermediates. PNAS, 2018, 115 (20), 5093-5098

BOOK of ABSTRACTS

MedChem2019




-15th

2019

97


Biological activity of toluquinol derivatives

José Antonio Torres-Vargas,a Iván Cheng-Sánchez,b Beatriz Martínez-Poveda,a Miguel Ángel Medina,a,c Francisco Sarabia,b Ana R. Quesadaa,b

a Departamento Biología Molecular y Bioquímica, Facultad de Ciencias e IBIMA, Universidad de Málaga, Andalucía Tech, Málaga, España,

b Universidad de Málaga, Andalucía Tech, Departamento de Química Orgánica, Facultad de Ciencias, Málaga, España,

c U741 (CB06/07/0046) CIBER de Enfermedades Raras, Málaga, España


Toluquinol, a methylhydroquinone produced by a marine fungus, has already been described as a potent antitumoral and antiangiogenic compound. In this study the cytotoxic activity and the antiangiogenic potential of different derivatives of toluquinol have been evaluated in vitro. Cell proliferation assays (MTT method) have been carried out on a panel of endothelial and tumor cell lines, determining the IC50 values of the compounds. The capability of toluquinol derivatives to interfere in different steps of angiogenesis has also been determined, by studying their ability to inhibit the formation of endothelial tubule-like structures on Matrigel and to decrease migratory potential of endotelial cells. Our results show that certain structural modifications of toluquinol produce significant changes in the toxicity against cancer and endothelial cells, also affecting the antiangiogenic activity in vitro, as compared with the original compound. These data suggest that structural modification of toluquinol could help to obtain either more active or less toxic drug candidates for the treatment of angiogenesis dependent malignancies.

This work was supported by grants PIE P12-CTS-1507 (Andalusian Government and FEDER) and BIO2014-

56092-R (MINECO and FEDER). The “CIBER de Enfermedades Raras” is an initiative from the ISCIII (Spain).

BOOK of ABSTRACTS

MedChem2019




-15th

2019

98


In silico studies for the discovery of MUC1/CIN85 protein-protein interaction inhibitors as anti-metastatic agents

Serena Vittorio,a Rosaria Gitto,a Arthur Garon,b Ugo Perricone,c Thierry Langer,b and Laura De Lucaa a Department CHIBIOFARAM Polo Universitario SS. Annunziata, Università di Messina, Viale Palatucci, I-98168-

Messina, Italy. b Department of Pharmaceutical Chemistry, Faculty of Life Sciences, University of Vienna, Althanstraße 14, 1090-

Vienna, Austria. c Drug Design Group, Fondazione Ri.MED, via Bandiera 11, 90145-Palermo, Italy.


MUC1 is a transmembrane glycoprotein overexpressed in most epithelial cancers. Its extracellular domain is characterized by the presence of a variable number of tandem repeats regions (VNTRs) highly glycosylated in physiological conditions. In tumor cells, VNTRs are hypo-glycosylated favoring the instauration of new protein-protein interactions that affect the intracellular signaling. CIN85, a multifunctional adaptor protein, interacts with the tumor form of MUC1 through its SH3 domains and this association promotes the invasiveness of cancer cells [1]. In this work, in silico approaches were used in order to identify MUC1/CIN85 protein-protein interaction inhibitors. The goal of our study was to identify compounds able to bind CIN85 SH3 domain preventing its binding to MUC1. For this purpose, the opening of transient pockets on CIN85 SH3A domain during 400 ns of molecular dynamic (MD) simulation has been investigated. Based on RMSD, the obtained snapshots were clustered and for each cluster a representative frame has been identified. The presence of druggable ligand binding pockets was probed for each representative frame leading to the identification of a putative binding site for small

molecules (Figure 1). Compounds from Asinex PPI library were docked into the identified pocket and MD simulations were carried out for the best scored hits in order to evaluate the stability of the ligand-protein complexes. Finally, the compounds that showed the best results in silico were selected for the biological screening in cancer cells.

[1] Cascio S., Farkas A.M., Hughey R.P. and Finn O.J.; Oncotarget 2013, 4, 1686- 1697.

Figure 1: Putative ligand binding

pocket (blue mesh) identified on

CIN85 SH3 domain.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

99


A new synthesized ache inhibitor induces H2S formation in the brain Nazlıcan Belen,a Elif Alancay,a Gulnur Sevin,a Sulunay Parlar,

b Vildan Alptuzunb and Gunay Yetik Anacaka

aDepartment of Pharmacology, Faculty of Pharmacy, Ege University, Izmir Turkey

aDepartment of Pharmaceutical Chemistry, Faculty of Pharmacy, Ege University, Izmir Turkey


The brain is highly susceptible to oxidative stress as a lipid-rich tissue with high oxygen consumption rate and oxidative stress is implicated in several mental disorders including alzheimer, depression, anxiety disorders, schizophrenia and bipolar disorder Plasma H2S levels were significantly lower in patients with schizophrenia [1]. Thus we investigated whether oxidative stress decreases H2S formation in brain. Beside last studies reveal a unique antagonistic action of H2S in anxiety-like behaviors and suggest that elevating H2S signaling in the brain may represent a novel approach for the treatment of depressive and anxiety disorders [2]. Thus we investigated pharmacological tools that can stimulate H2S formation in brain.

Previously we have shown that 1,4-dihydropiridine-benzylidenhidrazon derived C1 coded compound that we synthesized inhibits AChE, Aβ fibril formation and causes destruction of already formed fibrils (IC50: 0.27 µМ) (3) as well as relaxation of the vessels. Now we investigated the effect of oxidative stress induced by pyrogallol and/or C1 (10-5 M, 30 min) on H2S formation in mice brain homogenates by methylene blue assay. We have used CSE inhibitor PAG (10mM) or CSE+CBS inhibitor AOAA to test to test the effect is through H2S synthesis. We found that oxidative stress caused a strong inhibition of H2S formation in brain (p<0.001, paired t test, n=9). Next we investigated whether compound C1 can reverse the decreased H2S formation in oxidative stress in brain. We found that C1 can augment the decreased H2S formation significantly (p<0.01, paired t test, n=9) and this augmentation is reversed back by CSE inhibitor PAG slightly but with CSE+CBS inhibitor AOAA strongly. These results suggest the dominant role of CBS in the stimulator effect of C1 on H2S formation.

Thus we suggest that decreased level of H2S may contribute to the mental disorders where oxidative stress is decreased such as depression, alzheimer diseases and schizophrenia. Since the neuroprotective role of H2S has been confirmed, our result suggest additional therapeutical potential of the new synthesized compound C1 in such mental disorders including oxidative stress through inducing H2S formation.

Acknowledgement: We thank Turkish Scientific Research Council TUBITAK for the grant #114S448 and COST action CA15135.

1. Xiong JW et all. Psychopharmacology (Berl). 2018 Aug;235(8):2267-2274

2- Chen WL et all. Behav Pharmacol. 2013 Oct;24(7):590-7

3. Prinz M. et all. European Journal of Pharmaceutical Sciences, 2013, 49:603-613,.

BOOK of ABSTRACTS

MedChem2019




-15th

2019

100

Author index

Legend Prefix_# progressive number PE-PL Paul Ehrlich Plenary communication

PE-SC Paul Ehrlich short communication

CA-SC MuTaLig COST Action short communication

PC Paul Ehrlich and MuTaLig poster communication

Acquaviva R. CA-SC_11 ........................................................ 42

Alancay E. PC_47 .............................................................. 99

Alarcón H. PC_6 ................................................................ 58

Alcaro S. CA-SC_5 .......................................................... 36 CA-SC_6 .......................................................... 37 CA-SC_8 .......................................................... 39 PC_11 .............................................................. 63 PC_2 ................................................................ 54 PC_20 .............................................................. 72 PC_25 .............................................................. 77 PC_27 .............................................................. 79 PC_31 .............................................................. 83 PC_36 .............................................................. 88 PC_39 .............................................................. 91 PC_42 .............................................................. 94 PE-SC_5 ........................................................... 18

Alfonsi R. PE-SC_12 ......................................................... 25

Alptuzun V. PC_47 .............................................................. 99

Alterio V. PC_1 ................................................................ 53

Altomare C.D. CA-SC_2 .......................................................... 33 CA-SC_4 .......................................................... 35

Amata E. CA-SC_11 ........................................................ 42

Ambrosio F.A. PC_11 .............................................................. 63 PC_2 ................................................................ 54

Amodio N. PC_39 .............................................................. 91

Amorim R. PC_31 .............................................................. 83 PE-SC_3 ........................................................... 16 PE-SC_6 ........................................................... 19

Anacak G.Y. PC_47 .............................................................. 99

Angeli A. PC_22 ............................................................. 74

Angelone T. PC_30 ............................................................. 82

Araškov J. PC_15 ............................................................. 67

Arcone R. PC_12 ............................................................. 64

Arena E. CA-SC_11........................................................ 42

Artese A. CA-SC_8 .......................................................... 39 PC_20 ............................................................. 72 PC_25 ............................................................. 77

Astolfi A. PE-SC_2 .......................................................... 15

Ayoub J. PC_13 ............................................................. 65

Bagetta D. CA-SC_5 .......................................................... 36 PC_31 ............................................................. 83 PE-SC_1 .......................................................... 14

Balducci S. PE-SC_12 ........................................................ 25

Baranyai Z. PC_19 ............................................................. 71

Barbarossa A. PC_10 ............................................................. 62 PC_3 ............................................................... 55

Baronissi G. PC_4 ............................................................... 56

Barreca M.L. PE-SC_2 .......................................................... 15

Belen N. PC_47 ............................................................. 99

Benatti A.L. CA-SC_16........................................................ 47

Benfeito S. PC_8 ............................................................... 60 PE-SC_3 .......................................................... 16 PE-SC_6 .......................................................... 19

BOOK of ABSTRACTS

MedChem2019




-15th

2019

101

Berardozzi S. PE-SC_12 ......................................................... 25

Bernardi F. PE-SC_12 ......................................................... 25

Bjelogrlić S. PC_15 .............................................................. 67

Boga R. PC_33 .............................................................. 85

Bonacci S. PC_12 .............................................................. 64 PC_23 .............................................................. 75 PC_28 .............................................................. 80 PC_44 .............................................................. 96

Bondi R. PC_17 .............................................................. 69

Bonesi M. PC_10 .............................................................. 62

Borges F. CA-SC_6 .......................................................... 37 PC_24 .............................................................. 76 PC_31 .............................................................. 83 PC_35 .............................................................. 87 PC_5 ................................................................ 57 PC_8 ................................................................ 60 PE-SC_3 ........................................................... 16 PE-SC_6 ........................................................... 19 PE-SC_9 ........................................................... 22

Borrell J.I. PC_37 .............................................................. 89 PC_6 ................................................................ 58 PE-SC_7 ........................................................... 20

Boshoff H.I. PE-SC_17 ......................................................... 30

Bősze S. PC_19 .............................................................. 71 PC_34 .............................................................. 86

Botta B. PE-SC_12 ......................................................... 25

Botta M. PE-SC_16 ......................................................... 29

Bou-Petit E. PC_6 ................................................................ 58

Bouton J. PC_7 ................................................................ 59 PE-SC_14 ......................................................... 27

Brescia C. PC_20 .............................................................. 72

Brunetti A. PC_25 .............................................................. 77

Bruno S. PC_34 ............................................................. 86

Bryant S.D. PC_29 ............................................................. 81

Buonanno M. PC_1 ............................................................... 53

Burke A.J. CA-SC_5 .......................................................... 36

Cagide F. PC_31 ............................................................. 83 PC_8 ............................................................... 60 PE-SC_6 .......................................................... 19

Caimano M. PE-SC_12 ........................................................ 25

Caljon G. PC_21 ............................................................. 73 PC_7 ............................................................... 59

Cannalire R. PE-SC_2 .......................................................... 15

Carradori S. CA-SC_3 .......................................................... 34

Carreiro E.P. CA-SC_5 .......................................................... 36

Caruso A. PC_3 ............................................................... 55

Casacchia T. PC_30 ............................................................. 82

Cascini G.L. PC_28 ............................................................. 80

Cassiano C. PC_4 ............................................................... 56

Catalano R. PC_25 ............................................................. 77 PC_39 ............................................................. 91 PC_9 ............................................................... 61

Catalanotti B. CA-SC_14........................................................ 45

Catto M. CA-SC_2 .......................................................... 33 CA-SC_4 .......................................................... 35

Cecchetti V. PE-SC_2 .......................................................... 15

Ceramella J. PC_10 ............................................................. 62 PC_3 ............................................................... 55 PC_30 ............................................................. 82

Chavarria D. CA-SC_6 .......................................................... 37 PE-SC_9 .......................................................... 22

BOOK of ABSTRACTS

MedChem2019




-15th

2019

102

Cheng-Sánchez I. PC_45 .............................................................. 97

Cho S.H. PE-SC_15 ......................................................... 28

Cirrincione G. PE-PL_1 ........................................................... 10

Collina S. PC_11 .............................................................. 63 PC_2 ................................................................ 54

Coricello A. PC_11 .............................................................. 63

Corigliano D.M. PC_25 .............................................................. 77

Costa G. CA-SC_8 .......................................................... 39 PC_11 .............................................................. 63 PC_2 ................................................................ 54 PC_20 .............................................................. 72 PC_25 .............................................................. 77 PC_27 .............................................................. 79 PC_39 .............................................................. 91 PC_42 .............................................................. 94

Costanzo P. PC_12 .............................................................. 64 PC_23 .............................................................. 75 PC_44 .............................................................. 96

Costi M.P. CA-SC_7 .......................................................... 38

Cottiglia F. CA-SC_10 ........................................................ 41 PC_16 .............................................................. 68 PC_26 .............................................................. 78

Cristofari C. CA-SC_9 .......................................................... 40

D’Agostino S. CA-SC_8 .......................................................... 39 PC_20 .............................................................. 72

D’Ambrosio K. PC_13 .............................................................. 65

D’Arca D. CA-SC_7 .......................................................... 38

Dalla Via L. PC_17 .............................................................. 69

da-Silva P.S. PC_5 ................................................................ 57

Dattilo V. CA-SC_8 .......................................................... 39 PC_20 .............................................................. 72

De Candia M. CA-SC_2 .......................................................... 33

De Luca L. PC_22 ............................................................. 74 PC_46 ............................................................. 98 PE-SC_4 .......................................................... 17

De Luca M. PC_30 ............................................................. 82

de Nazaré C Soeiro M. PC_21 ............................................................. 73

De Paolis E. PE-SC_12 ........................................................ 25

De Simone G. PC_1 ............................................................... 53 PC_13 ............................................................. 65

Della Volpe S. PC_2 ............................................................... 54

Deplano A. CA-SC_14........................................................ 45

Deplano S. CA-SC_10........................................................ 41 PC_26 ............................................................. 78

Deri B. PE-SC_4 .......................................................... 17

Di Fiore A. PC_13 ............................................................. 65

Di Giacomo C. CA-SC_11........................................................ 42

Di Gioia M.L. PC_23 ............................................................. 75 PC_44 ............................................................. 96

Di Leva F.S. PC_4 ............................................................... 56

Di Marcotullio L. PE-SC_12 ........................................................ 25

Dichiara M. CA-SC_11........................................................ 42

Distinto S. CA-SC_10........................................................ 41 PC_16 ............................................................. 68 PC_26 ............................................................. 78

Djokovic N. PC_14 ............................................................. 66

Doležal M. PC_18 ............................................................. 70

Eckerstorfer S. PE-SC_10 ........................................................ 23

Eder M. PE-SC_10 ........................................................ 23

BOOK of ABSTRACTS

MedChem2019




-15th

2019

103

Elek M. PC_14 .............................................................. 66

Era B. PC_26 .............................................................. 78

Esposito D. PC_1 ................................................................ 53

Estrada R. PC_6 ................................................................ 58

Estrada-Tejedor R. PC_37 .............................................................. 89

Fais A. PC_26 .............................................................. 78 PE-SC_4 ........................................................... 17

Felicetti T. PE-SC_2 ........................................................... 15

Fernandes C. CA-SC_6 .......................................................... 37 PC_24 .............................................................. 76 PC_35 .............................................................. 87 PC_5 ................................................................ 57 PC_8 ................................................................ 60 PE-SC_3 ........................................................... 16 PE-SC_6 ........................................................... 19 PE-SC_9 ........................................................... 22

Ferrari S. CA-SC_7 .......................................................... 38

Filipović N. PC_15 .............................................................. 67

Finamore C. PC_4 ................................................................ 56

Fiorucci D. PE-SC_16 ......................................................... 29

Fiorucci S. PC_4 ................................................................ 56

Fishman A. PE-SC_4 ........................................................... 17

Fiume G. PE-SC_5 ........................................................... 18

Floresta G. CA-SC_11 ........................................................ 42

Floris C. PC_16 .............................................................. 68

Floris S. PE-SC_4 ........................................................... 17

Fois B. CA-SC_10 ........................................................ 41 PC_16 .............................................................. 68 PC_26 .............................................................. 78

Fowler C.J. CA-SC_14........................................................ 45

Frank A. PC_14 ............................................................. 66

Franzblau S.G. PE-SC_15 ........................................................ 28

Garcia Argaez A.N. PC_17 ............................................................. 69

García-Sosa A.T. PE-SC_13 ........................................................ 26

Garofalo A. PC_30 ............................................................. 82

Garon A. PC_46 ............................................................. 98

Garrido J. PC_31 ............................................................. 83

Gaspar A. CA-SC_6 .......................................................... 37 PC_8 ............................................................... 60

Gattuso A. PC_30 ............................................................. 82

Gaudio E. CA-SC_8 .......................................................... 39 PC_20 ............................................................. 72 PC_42 ............................................................. 94

Germanò M.P. PE-SC_4 .......................................................... 17

Geronikaki A. PC_33 ............................................................. 85

Ghirga F. PE-SC_12 ........................................................ 25

Giacchè N. CA-SC_4 .......................................................... 35

Gil-Martins E. PC_24 ............................................................. 76

Gitto R. PC_22 ............................................................. 74 PC_46 ............................................................. 98 PE-SC_4 .......................................................... 17

Grande F. PC_3 ............................................................... 55 PC_30 ............................................................. 82

Granieri M.C. PC_30 ............................................................. 82

Grillone K. PC_39 ............................................................. 91

Guerrini R. CA-SC_7 .......................................................... 38

BOOK of ABSTRACTS

MedChem2019




-15th

2019

104

Guglielmi P. CA-SC_3 .......................................................... 34

Guijarro P.J. PC_6 ................................................................ 58

Hagenow S. CA-SC_1 .......................................................... 32

CA-SC_5 .......................................................... 36

Haider N. PE-SC_10 ......................................................... 23

Heffeter P. PE-SC_10 ......................................................... 23

Hulpia F. PC_21 .............................................................. 73

PC_7 ................................................................ 59

Hümmer S. PC_6 ................................................................ 58

Hyeraci M. PC_17 .............................................................. 69

Iaccino E. CA-SC_8 .......................................................... 39

PC_20 .............................................................. 72

PE-SC_5 ........................................................... 18

Iacopetta D. PC_10 .............................................................. 62

PC_3 ................................................................ 55

Ibric A. PE-SC_10 ......................................................... 23

Ielo L. PE-SC_4 ........................................................... 17

Infante P. PE-SC_12 ......................................................... 25

Ingallina C. PE-SC_12 ......................................................... 25

Ioele G. PC_30 .............................................................. 82

Jian Y. PE-SC_17 ......................................................... 30

Jochmans D. PC_16 .............................................................. 68

Juhás M. PC_18 .............................................................. 70

Juli G. PC_39 .............................................................. 91

Kaczor A.A. CA-SC_13 ........................................................ 44

Kartsev V. PC_33 .............................................................. 85

Krátký M. PC_19 ............................................................. 71

PC_34 ............................................................. 86

Kruschel R.D. PE-SC_11 ........................................................ 24

La Mantia A. CA-SC_11........................................................ 42

Labella L. PC_17 ............................................................. 69

Langella E. PC_13 ............................................................. 65

Langer T. PC_46 ............................................................. 98

Lanzillotta D. CA-SC_8 .......................................................... 39 PC_20 ............................................................. 72

Lauriola A. CA-SC_7 .......................................................... 38

Limongelli V. PC_4 ............................................................... 56

Lin C. PC_21 ............................................................. 73

Loizzo M.R. PC_10 ............................................................. 62

Lopez O. CA-SC_5 .......................................................... 36

Louko I. PE-SC_10 ........................................................ 23

Lucchetta M. CA-SC_19........................................................ 50

Lupia A. PC_25 ............................................................. 77 PC_27 ............................................................. 79 PC_42 ............................................................. 94 PE-SC_5 .......................................................... 18

Ma R. PE-SC_15 ........................................................ 28

Maccari G. PE-SC_16 ........................................................ 29

Maccioni E. CA-SC_10........................................................ 41 PC_16 ............................................................. 68 PC_26 ............................................................. 78 PC_40 ............................................................. 93

Machado D. PE-SC_2 .......................................................... 15

Maes L. PC_21 ............................................................. 73 PC_7 ............................................................... 59

BOOK of ABSTRACTS

MedChem2019




-15th

2019

105

Maisano D. PE-SC_5 ........................................................... 18

Mancuso F. PC_22 .............................................................. 74

Mancuso S. PC_23 .............................................................. 75

Manfroni G. PE-SC_2 ........................................................... 15

Mangani S. CA-SC_7 .......................................................... 38

Marian B. PE-SC_10 ......................................................... 23

Marino T. CA-SC_15 ........................................................ 46 PC_32 .............................................................. 84 PC_40 .............................................................. 92

Marković S. PC_15 .............................................................. 67

Marques C.S. CA-SC_5 .......................................................... 36

Marrazzo A. CA-SC_11 ........................................................ 42

Martínez-Poveda B. PC_45 .............................................................. 97

Martins C. PE-SC_3 ........................................................... 16

Martins D. PC_24 .............................................................. 76

Maruca A. PC_25 .............................................................. 77 PC_39 .............................................................. 91

Marverti G. CA-SC_7 .......................................................... 38

Marx F. CA-SC_17 ........................................................ 48

Massari S. PE-SC_15 ......................................................... 28 PE-SC_2 ........................................................... 15

Masullo M. PC_12 .............................................................. 64

Matosiuk D. PC_43 .............................................................. 95

Mazzarella M.A. PE-SC_15 ......................................................... 28

Mazzei A. CA-SC_20 ........................................................ 51

McCarthy F.O. PE-SC_11 ......................................................... 24

Medina M.Á. PC_45 ............................................................. 97

Meleddu R. CA-SC_10........................................................ 41 PC_16 ............................................................. 68 PC_26 ............................................................. 78 PC_40 ............................................................. 93

Mesiti F. CA-SC_6 .......................................................... 37

Mimmi S. CA-SC_8 .......................................................... 39 PC_20 ............................................................. 72 PE-SC_5 .......................................................... 18

Monti M.C. PC_4 ............................................................... 56

Monti S.M. PC_1 ............................................................... 53

Moraca F. CA-SC_14........................................................ 45 PC_25 ............................................................. 77 PC_27 ............................................................. 79 PE-SC_5 .......................................................... 18

Morgillo C.M. CA-SC_14........................................................ 45

Mori M. PE-SC_12 ........................................................ 25

Muller C.D. PC_15 ............................................................. 67

Müller C.E. PE-PL_2 .......................................................... 12

Munier-Lehmann H. PE-SC_17 ........................................................ 30

Nardi M. PC_12 ............................................................. 64 PC_23 ............................................................. 75 PC_44 ............................................................. 96

Neyts J. PC_16 ............................................................. 68

Nikolic K. PC_14 ............................................................. 66

Nizi M.G. PE-SC_15 ........................................................ 28

Novelli P. PC_28 ............................................................. 80

Novellino E. CA-SC_14........................................................ 45 PC_4 ............................................................... 56

Oblak D. PC_29 ............................................................. 81

BOOK of ABSTRACTS

MedChem2019




-15th

2019

106

Occhiuzzi M.A. PC_3 ................................................................ 55

PC_30 .............................................................. 82

Oliveira C. PC_31 .............................................................. 83

PC_8 ................................................................ 60

PE-SC_6 ........................................................... 19

Oliveira P.J. PC_31 .............................................................. 83

PE-SC_3 ........................................................... 16

PE-SC_6 ........................................................... 19

PE-SC_9 ........................................................... 22

Oliverio M. PC_12 .............................................................. 64 PC_23 .............................................................. 75 PC_28 .............................................................. 80 PC_44 .............................................................. 96

Oljacic S. PC_14 .............................................................. 66

Onnis V. CA-SC_14 ........................................................ 45

Orofino F. PE-SC_16 ......................................................... 29

Ortuso F. CA-SC_3 .......................................................... 34 PC_25 .............................................................. 77 PC_31 .............................................................. 83 PC_9 ................................................................ 61 PE-SC_5 ........................................................... 18

Pace V. PE-SC_8 ........................................................... 21

Pacifico S. CA-SC_7 .......................................................... 38

Paonessa R. PC_12 .............................................................. 64 PC_28 .............................................................. 80

Parise A. PC_32 .............................................................. 84

Parlar S. PC_47 .............................................................. 99

Pazy Y. PE-SC_4 ........................................................... 17

Pellicanò T.M. PC_10 .............................................................. 62

Perricone U. PC_46 .............................................................. 98

Petrou A. PC_33 .............................................................. 85

Petzer J.P. CA-SC_3 .......................................................... 34

Pflégr V. PC_34 ............................................................. 86

Pinto M. PC_35 ............................................................. 87 PE-SC_3 .......................................................... 16

Pintus F. PC_26 ............................................................. 78

Pinzi L. CA-SC_16........................................................ 47

Pisani L. CA-SC_2 .......................................................... 33 CA-SC_4 .......................................................... 35

Pitucha M. CA-SC_13........................................................ 44

Podlipnik Č. PC_29 ............................................................. 81

Ponterini G. CA-SC_7 .......................................................... 38

Prejanò M. CA-SC_15........................................................ 46 PC_40 ............................................................. 92

Prezzavento O. CA-SC_11........................................................ 42

Procopio A. PC_12 ............................................................. 64 PC_23 ............................................................. 75 PC_28 ............................................................. 80 PC_44 ............................................................. 96

Procopio A.C. PC_27 ............................................................. 79 PC_36 ............................................................. 88

Procopio F. PC_20 ............................................................. 72

Puig de la Bellacasa R. PC_37 ............................................................. 89

Quesada A.R. PC_45 ............................................................. 97

Quinto I. PE-SC_5 .......................................................... 18

Ramón Y Cajal S. PC_6 ............................................................... 58

Ramsay R.R. CA-SC_1 .......................................................... 32

Rapisarda A. PE-SC_4 .......................................................... 17

Rapposelli S. PC_42 ............................................................. 94

BOOK of ABSTRACTS

MedChem2019




-15th

2019

107

Rastelli G. CA-SC_16 ........................................................ 47

Remião F. PC_31 .............................................................. 83 PE-SC_3 ........................................................... 16 PE-SC_6 ........................................................... 19 PE-SC_9 ........................................................... 22

Risseeuw M.D.P. PE-SC_17 ......................................................... 30

Ritacca A.G. PC_38 .............................................................. 90

Rivela J. PC_37 .............................................................. 89

Rizzuti B. PC_3 ................................................................ 55 PC_30 .............................................................. 82

Rocca C. PC_30 .............................................................. 82

Rocca R. PC_25 .............................................................. 77 PC_39 .............................................................. 91 PC_42 .............................................................. 94

Roleira F.M.F. PC_27 .............................................................. 79

Romeo I. CA-SC_8 .......................................................... 39 PC_20 .............................................................. 72 PC_40 .............................................................. 92

Rossi D. PC_11 .............................................................. 63

Rotondi G. CA-SC_3 .......................................................... 34

Rullo M. CA-SC_2 .......................................................... 33 CA-SC_4 .......................................................... 35

Russo N. CA-SC_15 ........................................................ 46 PC_32 .............................................................. 84 PC_38 .............................................................. 90 PC_40 .............................................................. 92

Sabatini S. PE-SC_2 ........................................................... 15

Sala F. PC_11 .............................................................. 63

Samaritani S. PC_17 .............................................................. 69

Sarabia F. PC_45 .............................................................. 97

Sarmento B. PE-SC_3 .......................................................... 16

Saturnino C. PC_10 ............................................................. 62 PC_3 ............................................................... 55

Sbardella G. CA-SC_18........................................................ 49

Scala G. PE-SC_5 .......................................................... 18

Schueffl H.H. PE-SC_10 ........................................................ 23

Secci D. CA-SC_3 .......................................................... 34

Senderowitz H. CA-SC_12........................................................ 43

Sepe V. PC_4 ............................................................... 56

Sequeira L. CA-SC_10........................................................ 41 PC_40 ............................................................. 93 PC_5 ............................................................... 57

Sestito S. PC_42 ............................................................. 94

Sevin G. PC_47 ............................................................. 99

Sicari V. PC_10 ............................................................. 62

Sicilia E. PC_38 ............................................................. 90

Silva C. PC_24 ............................................................. 76

Silva R. PC_24 ............................................................. 76 PC_5 ............................................................... 57 PE-SC_6 .......................................................... 19

Silva T. PC_24 ............................................................. 76 PC_31 ............................................................. 83

Silva V. PC_5 ............................................................... 57

Sinicropi M.S. PC_10 ............................................................. 62 PC_3 ............................................................... 55

Sissi C. CA-SC_9 .......................................................... 40

Soares C. PC_35 ............................................................. 87

Soares P. PC_24 ............................................................. 76

BOOK of ABSTRACTS

MedChem2019




-15th

2019

108

Stark H. CA-SC_5 .......................................................... 36

PC_14 .............................................................. 66 Statti G.

PC_30 .............................................................. 82 Stolaříková J.

PC_34 .............................................................. 86 Straszak D.

PC_43 .............................................................. 95 Supuran C.T.

CA-SC_10 ........................................................ 41 PC_1 ................................................................ 53 PC_13 .............................................................. 65 PC_22 .............................................................. 74

Tabarrini O. PE-SC_15 ......................................................... 28 PE-SC_2 ........................................................... 15

Tagliaferri P. PC_39 .............................................................. 91

Talarico C. PE-SC_5 ........................................................... 18

Tallarico S. PC_44 .............................................................. 96

Tassone P. PC_39 .............................................................. 91

Tavares da Silva E.J. PC_27 .............................................................. 79

Teixeira J. PC_31 .............................................................. 83 PE-SC_3 ........................................................... 16 PE-SC_6 ........................................................... 19

Tiago S. PC_5 ................................................................ 57

Tinivella A. CA-SC_16 ........................................................ 47

Todorović T. PC_15 .............................................................. 67

Torres-Vargas J.A. PC_45 .............................................................. 97

Toscano S. PE-SC_12 ......................................................... 25

Trapasso F. CA-SC_8 .......................................................... 39 PC_20 ............................................................. 72 PC_42 ............................................................. 94

Tundis R. PC_10 ............................................................. 62

Tunjic L. PE-SC_10 ........................................................ 23

Uriarte E. PC_31 ............................................................. 83 PE-SC_6 .......................................................... 19

Van Calenbergh S. PC_21 ............................................................. 73 PC_7 ............................................................... 59 PE-SC_14 ........................................................ 27 PE-SC_17 ........................................................ 30

Van Hecke K. PC_21 ............................................................. 73

Vasile F. PC_11 ............................................................. 63 PC_2 ............................................................... 54

Vecchio E. PE-SC_5 .......................................................... 18

Villanueva A. PC_37 ............................................................. 89

Vinšová J. PC_19 ............................................................. 71 PC_34 ............................................................. 86

Vittorio S. PC_46 ............................................................. 98 PE-SC_4 .......................................................... 17

Viveiros M. PE-SC_2 .......................................................... 15

Wan B. PE-SC_15 ........................................................ 28

Winum J.Y. PC_13 ............................................................. 65

Zampella A. PC_4 ............................................................... 56

Zeidler R. PC_1 ............................................................... 53

Zitko J. PC_18 ............................................................. 70

Zivkovic A. PC_14 ............................................................. 66

book of abstracts medchem2019 catanzaromedchem2019.unicz.it/book_of_abstracts_medchem2019... ·...

Documents