3° Encontro Nacional de Quimica Terapeutica
3rct Portuguese Meeting on Medicinal Chemistry 1'1 Portuguese-Spanish-Brazilian Meeting on Medicinal Chemistry.
P27
Electrochemical behavior of hydroxyxanthones versus ROS and RNS scavenging activities
Clementina M. M. Santos,a,b M. Beatriz Q. Garcia,c Artur M. S. Silva,b Eduarda Fernandesc
"Department of Vegetal and Production Technology, School ofAgriculture, Polytechnic Institute of Braganfa, 5301-855 Bragan,·a, Portugal; ''Department of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal; cREQUIMTE, Department of Ch emical Sciences, Faculty of Pharmacy, University of
Porta, Rua de forge Viterbo Ferreira n." 228, 4050-313 Porta, Portugal
Xanthones are a class of naturally-occurring oxygenated heterocyclic compounds with a broad spectrum of biological activities of great interest for potential therapeutic applications. 1 IJ Thus, over the last decades a great number of publications have emerged focusing on the isolation and s~nthesis of these natural compounds or even in the search for novel bioactive derivatives.1- 1
Electrochemical methodologies can be applied to establish correlations between structure and oxidation potential of electroactive species and therefore to predict some of its biological activities. In fact, cyclic voltammetry has become an important and widely used electroanalytical technique in many relevant studies of redox ~rocesses for clarifying the electrochemical behavior of chemical and biochemical systems.1 1
Herein, we will report the electrochemical behavior of several phenolic and catecholic-substituted 2,3-diarylxanthones by cyclic voltammetry using a glassy carbon electrode, at pH 7.4, and the results obtained compared with their scavenging activities for reactive oxygen species (ROS) and reactive nitrogen species (RNS). 141 Useful considerations about oxidation mechanism will be highlighted and the electrochemical profile of xanthones will corroborate their biological propetties.
9.0
5.0
<t .:- 1.0
·3.0
·7.o.0.6 ·0.3 0.0 0.3 0.6 0.9
E I V (vs. Ag/AgCI)
Acknowledgments: Sincere thanks are expressed to Faculdade de Farmacia da Universidade do Porto, and to Universidade de Aveiro, Funda<;:ao para a Ciencia e a Tecno1ogia (Portugal) and FEDER for funding the Organic Chemistry Research Unit (project PEst-C/QUI/UI0062/20 11 ).
References [IJ (a) E1-Seedi, H.R. ; E1-Ghorab, D.M.H.; El-Barbary, M.A.; Zayed, M.F. ; Goransson, U.; Larsson, S. ;
Verpoorte, R. Curr. Med. Chem. 2009, /6, 2581. (b) Pinto, M. M. M.; Sousa, M. E.; Nascimento, M. S. J. Curr. M eel. Chem. 2005, / 2, 2517.
[2] (a) Pinto, M. M. M. ; Castanheiro, R. A. P. Curr. Org. Chem. 2009, 13, 1215. (b) Pinto, M. M. M. ; Sousa, M. E.; Curr. Med. Chem. 2005, /2 , 2447.
[3] Teixeira. J. G. ; Dias, C. B.; Teixeira, D. M. Electroanalysis 2009, 21 , 2345. (b) Boza1 , B. ; Us1u, B.; Ozkan, S. A. Int. J. Electrochemistry 2011 , 1. (c) Heinze, J. Angew. Clw n. lnt. Ed. Engl. 1984, 23, 831.
[4) Santos, C. M. M.; Freitas, M.; Ribeiro, D.; Gomes, A. ; Si1va, A. M. S. ; Cava1eiro, J. A. S. ; Fernancles, E. Bioorg. Med. Chem. 2010, 18, 6776.
1c and 3a Ipa / Ipc = 1
Electrochemical reversible process
Clementina M. M. Santos,a,b M. Beatriz Q. Garcia,c Artur M. S. Silvab and Eduarda Fernandesc aDepartment of Vegetal and Production Technology, School of Agriculture, Polytechnic Institute
of Bragança, 5301-855 Bragança, Portugal. Email: [email protected] bDepartment of Chemistry & QOPNA, University of Aveiro, 3810-193 Aveiro, Portugal cREQUIMTE, Department of Chemical Sciences, Faculty of Pharmacy, University of Porto,
Rua de Jorge Viterbo Ferreira n.º 228, 4050-313 Porto, Portugal
[1]. (a) El-Seedi, H.R.; El-Ghorab, D.M.H.; El-Barbary, M.A.; Zayed, M.F.; Göransson, U.; Larsson, S.; Verpoorte, R. Curr. Med. Chem. 2009, 16, 2581.
(b) Pinto, M. M. M.; Sousa, M. E.; Nascimento, M. S. J. Curr. Med. Chem. 2005, 12, 2517.
[2]. (a) Pinto, M. M. M.; Castanheiro, R. A. P. Curr. Org. Chem. 2009, 13, 1215. (b) Pinto, M. M. M.; Sousa, M. E.; Curr. Med. Chem. 2005, 12, 2447.
[3]. (a) Teixeira. J. G.; Dias, C. B.; Teixeira, D. M. Electroanalysis 2009, 21, 2345. (b) Bozal, B.; Uslu, B.; 蒐zkan, S. A. Int. J. Electrochemistry 2011, 1.
(c) Heinze, J. Angew. Chem. Int. Ed. Engl. 1984, 23, 831.
[4]. Santos, C. M. M.; Freitas, M.; Ribeiro, D.; Gomes, A.; Silva, A. M. S.; Cavaleiro, J. A. S.; Fernandes, E. Bioorg. Med. Chem. 2010, 18, 6776.
[5]. Santos, C. M. M.; Silva, A. M. S.; Cavaleiro, J. A. S. Eur. J. Org. Chem. 2009, 2642.
Sincere thanks are expressed to Faculdade de Farmácia da
Universidade do Porto, and to Universidade de Aveiro, Fundação
para a Ciência e a Tecnologia (Portugal) and FEDER for funding
the Organic Chemistry Research Unit (project PEst-
C/QUI/UI0062/2011).
Table 1
O2•-, 1O2, HOCl, •NO and ONOO- (with and without 25 mM NaHCO3) scavenging effects of the tested 2,3-
diarylxanthones and positive controls (IC50, mean ± SEM).
Compound
IC50 (ちM)
O2•- 1O2 HOCl NO•
ONOO- without
NaHCO3
ONOO- with
NaHCO3
2,3-diarylxanthones
1a NA25たM 27%*100たM 155 ± 25 39%*200たM 29%*50たM 48%*50たM
1b NA200たM 80 ± 11 72.1 ± 8.6 175 ± 36 1.55 ± 0.14 1.80 ± 0.39
1c 28.1 ± 2.3 6.0 ± 1.0 15.7 ± 1.1 1.88 ± 0.18 0.40 ± 0.03 0.54 ± 0.08
2a NA200たM 68.8 ± 6.2 53.8 ± 7.8 41%*200たM 2.66 ± 0.29 2.00 ± 0.15
2b 166 ± 16 58.4 ± 4.9 22.4 ± 2.5 108 ± 18 1.72 ± 0.21 0.97 ± 0.25
2c 20.3 ± 2.5 3.3 ± 0.7 14.7 ± 1.3 0.42 ± 0.05 0.26 ± 0.05 0.78 ± 0.26
3a 76 ± 11 4.5 ± 0.6 10.8 ± 0.4 1.22 ± 0.21 0.37 ± 0.09 0.67 ± 0.09
3b 31.3 ± 3.2 6.8 ± 0.5 7.5 ± 0.7 0.62 ± 0.10 0.22 ± 0.03 0.89 ± 0.18
3c 10.4 ± 0.8 2.5 ± 0.2 1.2 ± 0.02 0.39 ± 0.05 0.17 ± 0.01 0.33 ± 0.06
Positive controls
Tiron 273 ± 32 __ __ __ __ __
Quercetin __ 1.8 ± 0.1 __ __ __ __
Dihydrolipoic acid __ __ 2.3 ± 0.3 __ __ __
Rutin __ __ __ 2.53 ± 0.37 __ __
Ebselen __ __ __ __ 0.50 ± 0.03 2.01 ± 0.22
NANo activity was found up to the highest tested concentration (in superscript) *Scavenging effect (mean %) at the highest tested concentration (in superscript)
The oxidation peak at higher potential values can be attributed to the phenolic groups.
The absence of the corresponding reduction peaks also pointed to the irreversibility of the
redox reaction of the oxidized compounds generated in the forward scan.
Cyclic voltammograms of compounds 1c, 2c, 3a-c showed the permanent presence of a
low oxidation peak attributed to the catechol group oxidation, in an electrochemical
reversible process.
In the Pearson test, excellent correlations are observed for O2•−, •NO and ONOO−, as
expected for scavenging reactions involving electron transfer mechanisms. Significant
correlations are also found for HOCl and 1O2, highly reactive oxygen species which are
known for scavenging mechanisms involving structural features.
Xanthone 3c with two catechol units presented the lowest anodic potential voltage (Epa =
0.15 V) and proved to be the most effective ROS and RNS scavenger.
Scheme 1. Chemical structures of the studied 2,3-diarylxanthones
O
O
R2
R11a-c
O
O
OH
R2
R12a-c
O
O
OH
OH
R2
R13a-c
a) R1 = R2 = H
b) R1 = OH, R2 = H
c) R1 = R2 = OH
a) R1 = R2 = H
b) R1 = OH, R2 = H
c) R1 = R2 = OH
a) R1 = R2 = H
b) R1 = OH, R2 = H
c) R1 = R2 = OH
BC
D
E
A
Xanthones are a class of naturally-occurring oxygenated heterocyclic compounds presenting a broad spectrum of
biological activities of great interest for potential therapeutic applications [1]. Thus, over the last decades a great number
of publications have emerged focusing on the isolation and synthesis of these natural compounds or even in the search
for novel bioactive derivatives [2].
Electrochemical methodologies can be applied to establish correlations between structure and oxidation potential of
electroactive species and therefore to predict some of its biological activities. In fact, cyclic voltammetry has become an
important and widely used electroanalytical technique in many relevant studies of redox processes for clarifying the
electrochemical behavior of chemical and biochemical systems [3].
Herein, we report the electrochemical behavior of several phenolic and catecholic-substituted 2,3-diarylxanthones, by
cyclic voltammetry, using a glassy carbon electrode, at pH 7.4. The obtained results are then compared with their
scavenging activities for reactive oxygen species (ROS) and reactive nitrogen species (RNS) [4]. Useful considerations
about oxidation mechanisms are highlighted and the electrochemical profile of xanthones discussed in light of their
antioxidant properties.
Voltammetric experiments were carried out using an Autolab electrochemical system (Eco Chemie model PGSAT
10). Data were acquired using GPES (General Purpose Electrochemical System) software, version 4.9.
The working electrode was a glassy carbon electrode (GCE) (3.0 mm) whereas an Ag/AgCl (KCl 3 M) electrode
and a carbon electrode were used as reference and auxiliary electrodes, respectively. Before use in
electrochemical experiment and in order to obtain a clean renewed electrode surface, the glassy carbon working
electrode was hand-polished with a 0.075 たm alumina aqueous slurry using a polishing cloth and washed with
purified water.
Xanthones 1-3 were synthesized according to previously reported procedures [5] and the chemical structures are
presented in scheme 1. Stock solutions of 1a-c, 2a-c and 3a-c were prepared in DMSO and diluted in sodium
phosphate buffer solution pH 7.4 at the final concentration 0.1 mM, unless otherwise mentioned.
The cell volume was 10 mL and cyclic voltammograms were obtained in a single cycle performed at a scan rate
of 100 mV s-1, at room temperature. For the scan rate studies, the scanning speed varied from 10 to 200 mV s-1.
Voltammetric scans were recorded in the voltage range between -0.5 and +1.0 V versus Ag/AgCl.
0
40
80
120
160
200
240
0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70
O2.-
sca
ven
gin
g a
ctiv
ity
Epa / V
Pearson r = 0.9419 0
20
40
60
80
100
0.00 0.10 0.20 0.30 0.40 0.50 0.60 0.70
1 O2
scav
eng
ing
act
ivit
y
Epa / V
Pearson r = 0.7784 0
20
40
60
80
100
0.00 0.20 0.40 0.60 0.80
HO
Cl s
cave
ng
ing
act
ivit
y
Epa / V
Pearson r = 0.8383
0
40
80
120
160
200
0.00 0.20 0.40 0.60 0.80
NO
. sca
ven
gin
g a
ctiv
ity
Epa / V
Pearson r = 0.9680 0
1
2
3
0.00 0.20 0.40 0.60 0.80
ON
OO
- wit
h N
aHC
O3
scav
eng
ing
act
ivit
y
Epa / V
Pearson r = 0.8693 0
1
2
3
0.00 0.20 0.40 0.60 0.80
ON
OO
- wit
ho
ut
NaH
CO
3 sc
aven
gin
g a
ctiv
ity
Epa / V
Pearson r = 0.9623
-7.0
-5.0
-3.0
-1.0
1.0
3.0
5.0
7.0
9.0
-0.6 -0.4 -0.2 -1E-15 0.2 0.4 0.6 0.8 1
I / ち
A
E / mV vs. Ag/AgCl
2c 0.1 mM
inversion at 1.0 V
inversion at 0.5 V
-7.0
-5.0
-3.0
-1.0
1.0
3.0
5.0
7.0
9.0
-0.6 -0.4 -0.2 -1E-15 0.2 0.4 0.6 0.8 1
I / ち
A
E / mV vs. Ag/AgCl
3b 0.1 mM
inversion at 1.0 V
inversion at 0.5 V
-4.0
-2.0
0.0
2.0
4.0
6.0
-0.4 -0.2 0 0.2 0.4 0.6 0.8
I / ち
A
E / V vs. Ag/AgCl
1c 0.1 mM
3a 0.1 mM
-2.0
0.0
2.0
4.0
6.0
-0.4 -0.2 0 0.2 0.4 0.6 0.8 1
I / ち
A
E / mV vs. Ag/AgCl
1b 0.1 mM
2a 0.1 mM
2b 0.1 mM
-3.0
-1.0
1.0
3.0
5.0
7.0
9.0
11.0
-0.4 -0.2 0 0.2 0.4 0.6 0.8
I / ち
A
E / V vs. Ag/AgCl
3c 0.1 mM
Epa = 0.16 V
Epc = 0.12 V
Epa = 0.18 V
Epc = 0.14 V
Epa = 0.56 V
Epa = 0.64 V
Epa = 0.58 V
Epa1 = 0.16 V
Epa2 = 0.69 V
Epc = -0.12 V
Epa1 = 0.18 V
Epa2 = 0.65 V
Epc = -0.11 V
Epa1 = 0.15 V
Epa2 = 0.37 V
Epc = -0.06 V
Inversion of potential scan before the
second oxidation peak (at 0.5 V),
2c and 3b Ipa / Ipc = 1
Electrochemical reversible process
O
O
OH
OH
OH
OH3c
Lowest Epa value!
Compound 3c presents
the lowest IC50 values for all ROS and RNS tested!
Scheme 2. Correlations between the Epa at pH 7.4 and the scavenging activity against ROS and RNS of
hydroxyxanthones 1-3a-c.
3° Encontro Nacional de Quimica Terapeutica 3rd Portuguese Meeting on Medicinal Chemistry
151 Portuguese-Spanish-Brazilian Meeting on Medicinal Chemistry
Has participated at the 3'd Portuguese Meeting on Medicinal Chemistry and 1st Portuguese-Spanish-Brazilian Meeting on Medicinal Chemistry and has presented a poster communication entitled "Electrochemical behavior of hydroxyxanthones versus ROS and RNS scavenging activities"
Portugal, Aveiro, 28t11 to 3o'11 November 2012
~~ Prof. Artur M. S. Silva
Chairman
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