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J. Braz. Chem. Soc. , Vol. 19, No. 8, 1437-1449, 2008.Printed in Brazil - 2008 Sociedade Brasileira de Qumica

0103 - 5053 $6.00+0.00

*e-mail: helio.santos@u j .edu.br

Reactivity of 5a,6-Anhydrotetracycline Platinum(II) Complex with Biological Nucleophiles:a Theoretical Study

Bruna L. Marcial, a Luiz Antnio S. Costa, b Wagner B. De Almeida c and Hlio F. Dos Santos* ,a

a Ncleo de Estudos em Qumica Computacional, Departamento de Qumica, Universidade Federal de Juiz de Fora,36036-330 Juiz de Fora-MG, Brazil

b Escola Preparatria de Cadetes do Ar, Departamento de Ensino da Aeronutica, Comando da Aeronutica, Rua Santos Dumont, 149, 36205-970 Barbacena-MG, Brazil

c Laboratrio de Qumica Computacional e Modelagem Molecular, Departamento de Qumica,Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte-MG, Brazil

No presente artigo, mtodos tericos oram utilizados para o estudo da interao entre ocomplexo 5a,6-anidrotetraciclina-dicloro-platina(II) (AHTC-Pt) e os nucle los adenina (A),guanina (G), cistena (Cys) e metionina (Met). A espcie [Pt(AHTC)Cl(H2O)]+ oi consideradacomo reagente em todos os processos investigados. Os valores calculados paraGa,aq no nvelB3LYP/6-311+G(2d,p) oram 21,7 e 20,7 kcal mol-1para as interaes com A e G, respectivamente,os quais esto em acordo com o comportamento esperado, sendo a reao com G mais rpida(Gaexpt= 18,5 kcal mol-1 para G). Para os processos envolvendo os aminocidos, as barreiras deenergia calculadas oram 17,6 (Cys) e 18,5 kcal mol-1 (Met), as quais so ligeiramente menoresdo que os valores experimentais para a cisplatina (20,5 e 20,2 kcal mol-1, respectivamente). Essesresultados mostram que a reatividade do complexo AHTC-Pt comparvel a da cisplatina e,portanto, o mesmo pode ser considerado um sistema relevante para o desenvolvimento de novosagentes antitumorais.

This paper describes a theoretical analysis o the interaction between 5a,6-anhydrotetracycline

platinum(II) complex (AHTC-Pt) and some biological nucleophiles; adenine (A), guanine (G),cysteine (Cys) and methionine (Met). The aquated species [Pt(AHTC)Cl(H2O)]+ was taken asreagent or the processes studied here. For DNA bases (A and G), the calculated values orGa,aq at the B3LYP/6-311+G(2d,p) level were 21.7 and 20.7 kcal mol-1 or interaction with A and G,respectively, which are in accordance with the expected behavior o aster process involving G.These values are higher than the experimental activation energy or the parent compound cisplatin(18.5 kcal mol-1 or interaction with G). For the process involving the amino-acids, the barrierswere 17.6 (Cys) and 18.5 kcal mol-1 (Met), which are lower than the observed values or cisplatin(20.5 and 20.2 kcal mol-1, respectively). These outcomes show that AHTC-Pt hybrid complex maybe considered a promising lead compound in the development o novel anticancer drugs basedon platinum complex.

Keywords: cisplatin analogues, tetracyclines,ab initio calculations

Introduction

Tetracyclines (TCs) constitute a amily o agentswith antimicrobial activity, which comprises natural andsemisynthetic analogues.1 These molecules are primarilyused as antibiotic in animal diseases, however somechemically modi ied tetracyclines (CMTs) have also

been ound to suppress the ormation and magnitude ometastases associated with certain cancers.2 The activeTCs have a general structure with the used tetracyclenatural con guration o chiral centers and the presence othe essential dimethylamino group at position C4 (Scheme1). The removal o this group eliminates the antimicrobiaactivity, as desired or some CMTs.1,2 The acquiredbacterial resistance has been the main problem with thesedrugs, responsible to shi t o most o the representativ

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Reactivity o 5a,6-Anhydrotetracycline Platinum(II) Complex with Biological Nucleophiles J. Braz. Chem. Soc.1438

rom human chemotherapy. The resistance mechanismshave been well understood with two main routes beingestablished, which are the decreasing in the drug uptakeand the activation o pumps that drive out drugs romcells.3-6Besides these overall descriptions, some molecular

eatures are described as coordination with divalent metalions, mainly Mg(II).3-6

The strong chelating ability o TCs has motivated theresearchers to search or novel inorganic complexes thatcould be used to overcome resistance and side e ects o thedrugs.7-12Mg(II) and Ca(II) are the main ions coordinatedto the ree raction o the drug,7,10nonetheless the transitionmetals complexes have also been o interest.8,9,11,12 The5a,6-anhydrotetracycline platinum(II) complex (AHTC-Pt) was rstly synthesized by Alyet al. ,9 who assigned thecoordination site on the ring A. A terwards, Pereira-Maiaand collaborators11 reported the Pt(II) complex with theparent compound TC and some o its analogues, nameddoxycline, oxytetracycline and chlortetracycline.12 Thelatter species were tested against sensitive and resistant

E. Coli strains, proving to be more potent than the reeantibiotic against resistant strains.12 All the complexesobtained so ar have a general stoichiometry [Pt(TC)Cl2]with Pt(II) bound to O3-Oam on ring A (Scheme 2). Despitethe greater interest in antibiotic activity, the complex o TCs with Pt(II) may also be viewed as a cisplatin analogue,where the vector ligand (TCs) should remain coordinatedto the Pt center throughout the whole process leading tointeraction with the nal target DNA. The presence o TCsligand certainly will modi y signi cantly the physical-chemistry properties o the drug and the DNA binding

mode.13

For fat derivatives, such as the BCD ring systemin AHTC (see Scheme 1), the intercalation may also playa role on DNA binding, there ore the AHTC-Pt might

be expected to act as a hybrid metalating-intercalatingagent.14,15

In the last ew years our group has given a contributionto the tetracycline16-23 and cisplatin23-28 computationalchemistry, investigating structures, spectroscopy andreactivity o ree ligand and complexed orms. Thesestudies have assisted the experimentalist to elucidatethe coordination modes o TCs with some metal ions asMg(II), Zn(II), Al(III) and Pt(II), as well as, quanti yingthermodynamic and kinetic properties o important reactiveprocesses. For the AHTC-Pt complex, our previous paper23 clari ed on quantitative basis the coordination o the metalin the ring A. Among 14 distinct complexation modes,we proposed an equilibrium between structures IVAand VA (Scheme 2), slightly shi ted toward VA (Gaq =1.2 kcal mol-1). The comparison between experimental andtheoretical NMR data supported the presence o orm IVAin larger amount in the medium. In addition to the structuresand spectroscopic properties, we also analyzed the aquationreaction, showing that the AHTC-Pt compound reacts withwater at similar rate as cisplatin does. In aqueous solutionthe second-order rate constant is (in mol-1L s-1): 4.510-6 orAHTC-Pt and 2.5-8.510-5 or cisplatin (experimental value

rom re erences 29-31). This is an important result, whichputs the AHTC-Pt complex as a promising lead compoundin developing new cisplatin analogues. Following thisobservations, the next step is to evaluate the reactivity o this complex with other important biological nucleophiles,representing proteins and nucleic acid. In the present workwe explore, by means o theoretical calculations, thepotential energy sur ace (PES) or the reaction o AHTC-

Pt aquated species, [Pt(AHTC)Cl(H2O)]+

, with sul ur-containing amino acids methionine (Met) and cysteine(Cys) and DNA bases guanine (G) and adenine (A). Thereaction paths are completely described given structuresand spectroscopic properties o reactive species in additionto the thermodynamic and kinetic quantities.

Theoretical Details

The reaction considered in the present work isrepresented in equation 1, where Nu stands or thenucleophiles: Met, Cys, A and G.

OOOH OH

CH3HOH H

OH

NH(CH3)2

O-

O

NH2

+

ABCD

12

34

4a12a

5

5a6

6a

78

910

10a11

11a12

OOHOH O

H

OH

NH(CH3)2

O-

O

NH2

+

ABCD

12

34

4a12a

5

5a6

6a

78

910

10a11

11a12

CH3

H+

-H3O+

TC AHTC

Scheme 1. Structures o tetracycline (TC) and its anhydrous derivative (AHTC). The numbering scheme used herein is indicated.

O

H

OH

NH(CH3)2

O-

O

NH2

+

A

12

34

4a12a

PtClCl

O

H

OH

NH(CH3)2

O-

NH2

O

+

A

12

34

4a12a

Pt

Cl

ClDGaq=-1.2 kcal/mol

IVA VA

Scheme 2. Most avorable AHTC-Pt complexes proposed in our previouspaper. The coordination site IVA is supported by experimental ndings.

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Marcialet al. 1439Vol. 19, No. 8, 2008

[Pt(AHTC)Cl(H2O)]+ + Nu [Pt(AHTC)Cl(Nu)]++ H2O (1)

The AHTC ligand, in the aquated species [Pt(AHTC)Cl(H2O)]+, is on the neutral zwitterionic state (LH2)23 and

the coordination mode was chosen as IVA (see Scheme 2).The amino acids structures with COOH and NH2 groupswere used as described previously or cisplatin parentcompound.28

The kinetic properties were calculated within thesupermolecule approach, where reagents and productsare treated as molecular complexes. These species (calledherea ter intermediates I-1 and I-2 or reagent and product,respectively) are located on the PES or each exchangeligand process through intrinsic reaction coordinate (IRC)calculation,32 starting rom transition state (TS) structures.This procedure ensures the true species participating in thereaction pathway. An associative mechanism is assumed

or all processes analyzed, with the TS represented by adistorted bipyramidal-trigonal geometry.

The geometries o all reactive molecules, includingreagents, products, intermediates and transition states,where ully optimized in gas phase at the Hartree-Fock(HF) and density unctional theory (DFT), with theB3LYP unctional,33,34 using standard split-valence basissets with additional polarization unctions on heavy atoms(6-31G(d)). For platinum atom, the e ective core potentialo Hay and Wadt35were used or core atomic orbitals and thecorresponding double-zeta basis-set or valence shell (thisis speci ed by the label LanL2DZ). The structures were

urther characterized either as minimum (no imaginaryrequency) or rst-order TS (only one imaginary requency)

on the PES by means o harmonic requency analysis. Theactivation ree energy in gas phase (Ga,g) was calculatedby equation 2, whereEa,gele-nuccomes rom the electronicplus nuclear contribution andGTa,g rom thermal correctionat 25 C and 1atm.

Ga,g = Ea,gelenuc+ GTa,g (2)

In order to investigate the role played by the basis-seton the energy pro le, single point calculation was alsoper ormed with enhanced basis-set (6-311+G(2d,p)). Atthis level o theory the ree energy values are calculatedthrough equation 2, but using the corresponding valueso the electronic plus nuclear contribution obtained at theB3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level (doubleslash means single point calculation). The thermodynamicand kinetic quantities were also calculated in water solution(r= 78.39) using the polarizable continuum model (PCM)within the integral equation ormalism (IEF).36 The gas

phase optimized geometries were considered or energycalculation in solution, with the solute cavity constructedaccording to the UAHF scheme,36including the electrostaticand non-electrostatic contributions to the solvation energyThe activation ree energy in solution is given by equatio

3, where the last term on the right hand is the di erencin solvation energies or TS and intermediate adductcalculated at the same level as the geometry.

Ga,aq = Ga,g + dGasolv (3)

The calculations were carried out using Gaussian 03revision D.0137 with the convergence criteria set as thede ault o the program.37

Results and Discussion

The structure o [Pt(AHTC)Cl2] complex and itshydrolysis process, leading to [Pt(AHTC)Cl(H2O)]+ aquatedspecies, were previously discussed.23 The main outcome

rom that work was the unambiguous characterization o thcoordination mode through1H and13C NMR analyses. Twoalmost degenerated orms were proposed as represented iScheme 2, with IVA tting better the experimental data.This orm was used in the present work to describe thereaction 1. In this rst part o the paper the structures anNMR spectra or the products, [Pt(AHTC)Cl(Nu)]+ (Nu =G, A, Cys, Met), are discussed based only on theoreticalresults, once experimental in ormation is not available such molecules. We hope that the ollowing results mayassist the experimentalist in uture studies, identi yinadducts ound in tetracyclines and biomolecules mixtureseven though very simple molecular models are used hereas nucleophiles.

Table 1 collects the structural parameters around metalcenter, where the numbering sequence given in Scheme 1was used. Firstly analyzing the coordination shell, it canbe noted that the metal geometry is close to square-planar

or all complexes, withX(Nu)-Pt-Cl andX(Nu)-Pt-O3

bond angles in the range o 87-94 and the torsiondX-O3-Oam-Cl ound equal to 180-187. The slightly greater ouo -plane distortion ound or G (7) is due the two weelectrostatic interactions involving the carbonyl at positionC6 o G with the methyl groups rom dimethylamoniummoiety in AHTC (see Figure 1). The shortest distancesbetween these groups were calculated to be 2.47 and 2.13 For A this interaction is also observed with the distancebetween methyl groups and NH2 at position C6 ound to be2.69 (see Figure 1). We do not expect a signi cant e eo these interactions on the stability o complexes, but theshould a ect on a measurable amount the NMR spectra,

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will be discussed latter. The main changes in the structureo the products are on the rPt-X bond lengths, which areclose to 2.0 or A and G complexes and close to 2.3

or Cys and Met compounds. The ring A o AHTC, whichis directly involved in the coordination with metal ion, also

shows similar geometries or the distinct complexes, witha canonical structure or the tricarbonyl system de ned bylonger C3-O3 and Cam-Oam bonds (ca. 1.28 ) comparedto C1-O1 (1.24 ) and shorter C3-C2 bond (1.41 ) thanC2-C1 (1.45 ), regardless the type o nucleophile.

The NMR spectra were calculated at the B3LYP/6-311+G(2d,p)//B3LYP/6-31G(d) level by using the Gauge-Independent Atomic Orbital (GIAO) method38that provides1H and13C magnetic shielding constants (). The chemicalshi ts or selected atoms were obtained on thed-scalerelative to TMS through equation 4,

di = TMS i (4)

where the values o TMS= 182.4656 or C andTMS=31.8821 or H were obtained at B3LYP/6-311+G(2d,p)level o theory. The relative chemical shi ts or the mainatoms on the ring A o ligand are represented in Figure 2.

Table 1. Structural parameters calculated at the B3LYP/6-31G(d)/ LanL2DZ level o theory or the distinct complexes [Pt(AHTC)Cl(Nu)]+.The bond lengths (r) are in and bond () and torsion (d) angles indegrees. The numbering sequence used is given in Scheme 1

Nu

Cys Met A GrPt-X(Nu) 2.32 2.33 2.02 2.05

rPt-Cl 2.34 2.34 2.33 2.34

rPt-O3 2.06 2.07 2.07 2.05

rPt-Oam 2.04 2.05 2.03 2.03

rC3-O3 1.28 1.28 1.28 1.27

rC2-C3 1.41 1.41 1.41 1.41

rC2-Cam 1.49 1.48 1.48 1.48

rCam-Oam 1.27 1.27 1.27 1.27

rC2-C1 1.47 1.47 1.47 1.47

rC1-O1 1.23 1.23 1.23 1.23X(Nu)-Pt-Cl 87.9 88.7 88.6 89.3

X(Nu)-Pt-O3 92.8 94.0 91.9 93.5

Cl-Pt-Oam 89.9 88.8 90.5 88.3

O3-Pt-Oam 89.2 88.3 88.8 88.9

dX-O3-Oam-Cl 180 180 181 187

Figure 1. B3LYP/6-31G(d)/LanL2DZ optimized geometries or the complexes [Pt(AHTC)Cl(Nu)]+ with Nu = G, A, Cys and Met, indicated in the gure.Some structural parameters are given in Table 1.

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The absolute values calculated or the ree ligand (notshown) were used as re erence. It should be pointed out thatthe chemical shi ts or ree AHTC calculated at B3LYP/6-311+G(2d,p) level are slightly di erent rom those given inre erence 23 calculated at B3LYP/6-311+G(d,p). Looking at

Figure 2 we see that the NMR spectra are not very sensitiveto the type o nucleophile, showing the same general pro leor all complexes. From Figure 2a it can be seen that most

o the carbon atoms in the ring A display down eld shi trelative to the ree ligand, with larger values calculated orC3 and Camd, which belong to the groups directly boundto the metal. For these atoms the average absolute chemicalshi ts, taking the our complexes studied, were 184 (C3) and175 ppm (Camd), being the values or G and A complexesslightly higher (185 and 176, respectively). For the reeAHTC, the respective calculated chemical shi ts are 176.4(C3) and 169.2 (Camd), which agree within 5% with theexperimental data.39 This nice agreement suggests that inthe absence o experimental data, the calculated absoluteand relative (Figure 2a) chemical shi ts may be used asguide in the characterization o the complexes. Nonetheless,bearing in mind the precision o 5%, we can not preciselyassign the13C NMR to distinguish between complexes withdi erent nucleophiles analyzed.

The1H NMR chemical shi ts depicted in Figure 2b alsoshow important eatures that might be used to identi y the

structures o the complexes. The hydrogen atoms in thdimethylamonium (DMA) moiety are a ected in di erways depending on the type o nucleophile. Taking theaverage chemical shi t or each methyl group, we oud equal to 2.8 ppm or both CH3 in the ree ligand. This

outcome is in per ect accordance with the experimentainding11 that showed only one peak at 2.9 ppm. Thetheoretical data or the coordinate Pt(II) complexes withCys and Met also give only one average value at 2.8 ppmthere ore showing a similar1H NMR spectrum to theligand in what the DMA group is concerned. For G and Aa splitting o these signals are predicted rom 2.8 ppm t3.2 and 3.8 ppm (G) and to 2.8 and 3.3 ppm (A), with thelower eld peak assigned to the methyl interacting withnucleophiles (see Figure 1). For G both CH3 groups areclose to the carbonyl at C6, thus a low eld shi t is oun

or both methyls, whereas or A only one methyl interacwith the NH2 at C6 (see Figures 1 and 2). It is opportuneto re er to our previous paper23 where we showed that even

or the [Pt(AHTC)Cl2] complex, coordinated in the modeIVA, a low eld shi t was obtained or the DMA methygroups. This is not only consequence o the AHTC-Pinteraction, but mainly due to a con ormational change ithe ligand rom twisted to extended (see re erence 17) upothe complex ormation, putting the CH3 and Cl groupscloser. This same extended orm was considered or a

Figure 2. 13C (a) and1H (b) relative chemical shi ts or the complexes [Pt(AHTC)Cl(Nu)]+ with Nu = G, A, Cys and Met, indicated in the gure. The valuesor the ree AHTC ligand were taken as re erence. The absolute chemical shi ts were calculated by means o equation 4.

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compounds analyzed here. At the level o theory used inthe present work (B3LYP/6-311+G(2d,p)), the signals o DMA in the [Pt(AHTC)Cl2] complex split to 2.5 and 3.5ppm, which is a very similar pattern to the spectrum ound

or A complex. There ore, we can conclude that this region

o the1H NMR spectrum can be taken as an important probein the characterization o the complexes.Be ore discussing the whole reaction path, it is opportune

to shortly analyze the thermodynamics o equation (1) or thedistinct nucleophiles. The gas phase data shows the G reaction asthe most avorable in gas phase withGR,gas= 22.9 kcal mol-1,

ollowed by Met (9.6 kcal mol-1), A (8.9 kcal mol-1) andCys (1.1 kcal mol-1). The inclusion o solvent changes thetrends, showing the Cys complexation as the most avorableprocess (GR,aq= 13.8 kcal mol-1). For the other reactions thepredicted ree energy in aqueous solution at the B3LYP/6-31G(d)/LanL2DZ level were 9.9 (G), 0.6 (A) and 1.6 kcalmol-1(Met). The results in aqueous solution are in qualitativeagreement with the expected behavior o more avorableprocesses or G than A and or Cys than Met.

The coordination o platinum to DNA bases is the keystep towards the biological action o platinum-based drugs.This link bends the helix axis to a substantial amount,inducing programmed cell death (apoptosis).40 Despitethe geometric aspects o complex, which directly inter erein the DNA binding, the kinetic actors play a primaryrole on the reaction pathway, considering the competitionwith several thermodynamically avorable side processesoccurring simultaneously in the biological medium.There ore, the understanding at a molecular level o theseprocesses is essential to rationalize new molecules withdesired biochemical properties.

Among the large number o theoretical studies publishedin the last ten years on the interaction o cisplatin likemolecules with DNA and sul ur-containing molecules, themost important o them are re erenced in the recent papers o

Burda and co-workers41,42and Dos Santos and co-workers.27,28 These articles deal with standard mode o action o cisplatin,where the rst step towards the ormation o bi unctionaladducts with DNA and proteins is the binding o monoaquaspecies with nucleophiles, as represented in equation 1. This

process is investigated herein or the AHTC-Pt complexocusing in kinetic properties, considering the purine bases(G and A) and the ree amino acids (Cys and Met) as thesimplest biological models. An associative mechanism isassumed or all reactions, passing through a pentacoordinatedtransition state. For G and A, the reactions involve thedisplacement o the aqua ligand o the chloroaqua complexby the N7 site o G or A. In the case o the amino acids, theentering ligand coordinates through the sul ur atom. TheB3LYP/6-31G(d)/LanL2DZ optimized geometries or TSGand TSA-1, participating in the water/purine-base exchangepathway, are depicted in Figure 3, with some calculatedstructural parameters quoted in Table 2.

Looking at Figure 3, we see that the structures proposedare the most hydrogen-bonded assisted, with the substituentat position C6 o the nucleophiles interacting with waterleaving ligand through a hydrogen bond. In TSG, water actsas proton donor with dHwO6 = 1.82 . This pattern isdi erent in TSA-1, where water is the proton acceptor group(dNH2Ow = 1.99 ). This di erence in the interactionmode between the leaving and the entering ligandspromotes a distortion in the geometry o the coordinationshell. The rPt-N7 and rPt-Ow bond lengths were 2.53 and2.43 or G and 2.60 and 2.51 or A, respectively. Thebond angleOw-Pt-N7 was larger or G (73.3) than orA (64.0), refecting directly on the degree o trigonality(), which is a structural index computed as in equation 5,where is the angle ormed by the axial ligands and thelargest angle on the equatorial plane.

= ( )/60 (5)

Figure 3. B3LYP/6-31G(d)/LanL2DZ optimized structures or the transition states (TS) involved in the binding o AHTC-Pt aquated species with pbases G and A. Some structural parameters are given in Table 2.

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For = 1 the metal center geometry can be viewed as aper ect D3htrigonal bipyramidal ( = 120 and = 180) and

or = 0 the geometry is assigned as C4v square pyramidal( = = 90).43 For the reaction with purine bases, were0.54 (G) and 0.46 (A), indicating an almost hal and hal mixture o square-pyramidal and trigonal bipyramidalgeometries or both transition states. These values are closeto those ound or the TS in the cisplatin reaction with = 0.53.27The spatial orientations o nucleophiles are alsoa ected due to the intramolecular hydrogen bond. Theangle between the equatorial plane o metal center, de nedby d in Table 2, and the plane o purine bases was equalto 58 or G and 95 or A, putting A perpendicular to thereaction center (see Figure 3). The structures shown inFigure 3 can be compared to those described in re erences

27 and 44. For the reaction o cisplatin aquated specieswith G27 the TS geometry was stabilized by a hydrogenbond between the axial NH3 and the carbonyl at C6. TherPt-N7 and rPt-Ow, calculated at the same level o theoryused in the present paper, were 2.53 and 2.42 ,27 in closeagreement with the values ound here (see Table 2). Thiswas also the case orOw-Pt-N7, ound equal to 73.1 inre erence 27. These geometrical similarities are expected,since the leaving and the entering ligands are the same. Themore pronounced di erence is on the spatial arrangemento G around metal center, which is primarily determined byinteraction with side chains in the AHTC vector ligand. The

TS or A binding to cisplatin diaqua species was describein re erence 44 where two pathways were proposed withthe pre erred one passing through a TS showing a hydrogebond between the NH2 moiety o A and the axial water.The level o theory used or geometry optimization wathe same as considered here, however, the authors observedintramolecular proton trans er rom water to NH2 upongeometry optimization, which was likely attributed to the+2 charge o diaquated cisplatin and the lack o solvent the calculations. Despite this non-physical phenomenon, thecalculated activation energy was in good accordance to theexperiment.44 The energy pro les or the whole reactionsstudies in the present paper will be described latter.

It is interesting to notice that the TS or purine-basesdescribed in the literature27,44 showed intramolecular

interactions with axial ligand. For the TS involving theAHTC-Pt complex and G and A, these are not avorable duto the nature o AHTC ligand (see Figure 3). The TSG showin Figure 3 may be considered unique, however or TSA twpossible structures may be thought having the water ligandacting either as proton acceptor (TSA-1 in Figure 3) or asproton donor (not shown). The optimized geometry or thlatter (named TSA-2) is similar to TSA-1 concerning thecoordination shell, with rPt-N7 and rPt-Ow ound to be 2.5and 2.44 , respectively. The angle between the enteringand the leaving ligands increases to 74.4, changing to 0.49. The hydrogen bond dHwNH2 was slightly

Table 2. Structural parameters calculated at the B3LYP/6-31G(d)/LanL2DZ level o theory or the intermediates (I-1 and I-2) and transition sinvolved in the reaction path or ormation o [Pt(AHTC)Cl(Nu)]+, where Nu stands or G and A. The bond lengths (r) are in and bond () and torsion(d) angles in degrees. The numbering sequence used is given in Scheme 1

G AI-1 TSG I-2 I-1 TSA-1 I-2

rPt-N7 4.22 2.53 2.03 3.88 2.60 2.02rPt-Ow 2.07 2.43 3.34 2.09 2.51 3.33rPt-Oam 2.00 2.03 2.03 2.00 2.00 2.03rPt-O3 2.05 2.05 2.07 2.05 2.04 2.05rPt-Cl 2.33 2.34 2.34 2.33 2.34 2.34

dHwO6a 1.69 1.82 1.99 - - -dNH2Owa - - - 2.16 1.99 1.88dHwN7a 1.82 - - 1.63 - -

Ow-Pt-N7 33.3 73.3 11.0 39.4 64.0 92.2

d:[N7-Pt-Oam-Ow] - 177.6 - - 174.9 -

b - 0.54 - - 0.46 -aIntermolecular distances in .bSee equation 5.

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relevant or nucleophiles like those studied here, whichlead to weakly bound complexes, possessing fat PES withmultiple minima pro le. The predicted bond lengths andangles or the intermediates I-1 and I-2 or all processes areincluded in Tables 2 and 3. From an overall analysis o theresults it can be clearly seen the variation o rPt-N7/S andrPt-Ow along the I-1 TS I-2 pathway, showing thePt-N7/S bond ormation and Pt-Ow bond breakage on theequatorial plane. Independent o the species analyzed thedi erence in bond lengths or purine-bases and amino acidscomplexes are mainly on the rPt-N7 and rPt-S, with thelatter longer than the ormer. Some intermolecular distancesare also shown or intermediate complexes, describing theattractive short contacts between the interacting species.The I-1 adducts ormed with purine bases are stabilizedby strong hydrogen bonds involving the coordinated waterand the N7 and C6 moieties o DNA bases. For I-1 in the

G process, two strong hydrogen bonds were computedwith dHwN7 and dHwO6 ound equal to 1.82 and1.69 , respectively. For A reaction only one relevanthydrogen bond was observed with dHwN7 = 1.63 .The intermediate I-1 participating in the reaction withCys and Met did not show any strong intermolecularinteraction, with the shortest contact ound or HwS,whose distance was about 2.2 in both cases. In the I-2species, the uncoordinated water molecule interacts withcomplex in di erent ways. For G, the water is hydrogenbonded to O6, with dHwO6 = 1.99 and or A adductthe water molecule acts as proton acceptor or NH2 at C6

and proton donor or Cl. The distances characterize bothhydrogen bond as short, being dNH2Ow = 1.88 anddHwCl = 2.39 .45For the amino acids a weak hydrogenbond is observed between water and Oam moiety o AHTCligand, with dHwOam2.1 . The optimized geometries

or the intermediates are not shown here, but are supplieas Supplementary In ormation.

Previous discussion de nes completely the structuraleatures or all species involved in the reactions pathway

which determines the energy pro les analyzed herea terFor A, Cys and Met that showed two distinct transitionstates, we calculated energy barriers or both processes ingas phase at the HF/6-31G(d)/LanL2DZ level o theoryThis procedure was the same used previously28 to decideabout the pre erred reaction path or Cys and Met bindinprocesses, with the choice being that giving the lowestenergy barrier. TheGa,gele-nucvalues at the HF level were

(in kcal mol-1

): 18.4 (TSA-1), 23.5 (TSA-2), 18.8 (TSC-1),41.6 (TSC-2), 18.6 (TSM-1) and 21.6 (TSM-2), showingthe TS-1 structures as those leading to the lowest energybarriers (see Figures 3 and 4). The greater di erence ou

or Cys processes is a consequence o the stability o Iound rom TSC-2 path, what is quite stable due to sho

hydrogen bonds. Based in our experiences with analoguesystems,27,28 we do not expect any change in this trend atthe DFT level, there ore the conclusion drawn rom Hcalculations may be taken as reliable with signi cantlylower computational cost compared to the B3LYP level.The geometric eatures or these structures and thei

Table 3. Structural parameters calculated at the B3LYP/6-31G(d)/LanL2DZ level o theory or the intermediates (I-1 and I-2) and transition sinvolved in the reaction path or ormation o [Pt(AHTC)Cl(Nu)]+, where Nu stands or Cys and Met. The bond lengths (r) are in and bond () andtorsion (d) angles in degrees. The numbering sequence used is given in Scheme 1

Cys MetI-1 TSC-1 I-2 I-1 TSM-1 I-2

rPt-S 4.24 2.85 2.32 4.46 2.88 2.32rPt-Ow 2.09 2.47 3.43 2.09 2.44 3.39rPt-Oam 1.99 2.03 2.05 2.00 2.04 2.06rPt-O3 2.05 2.04 2.06 2.04 2.04 2.07rPt-Cl 2.33 2.34 2.34 2.34 2.34 2.34

dHwSa 2.17 - - 2.16 - -

Ow-Pt-S 46.0 74.1 119.0 40.3 72.8 118.0

d:[S-Pt-Oam-Ow] - 172.8 - - 171.3 -

b - 0.46 - - 0.41 -aIntermolecular distances in .bSee equation 5.

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corresponding intermediates (I-1 and I-2) were discussedabove. Herea ter we ocus on the energy properties o the

our reactions analyzed, accounting or the interaction o [Pt(AHTC)Cl(H2O)]+ aquated species with purine bases (Gand A) and the amino acids (Cys and Met). Rememberingthat the reagents and products are treated as molecularcomplexes, the whole process can be represented by I-1 TS I-2, where the barrier rom I-1 TS is o primaryimportance, assuming a competition between the severalreactions.

All the contributions or ree energy barrier in gasphase (equation 2) and in aqueous solution (equation 3)are given in Table 4 at the B3LYP DFT level using twodistinct basis sets, 6-31G(d) and 6-311+G(2d,p). Theselevels o theory have been used in our previous papers

or cisplatin analogues,23,28 given energy barriers within1 kcal mol-1on average rom experimental data. There ore,we are con dent o the values reported here, without needto improve the level o calculation. Firstly analyzing the gas

phase data we see that reactions with amino acids are asterthan with purine bases. For Cys and Met binding the reeenergy barriers were 19.3 and 18.2 kcal mol-1, respectively,compared to 20.9 (A) and 20.2 kcal mol-1 (G) (B3LYP/6-31G(d)/LanL2DZ values). These values are close to theelectronic plus nuclear energy change (Ea,gele-nuc), withthermal correction contribution ound to be less than 2%

or A, Cys and Met. For G process, theGTa,g quantitycontributes with 7% decreasing the barrier, which is largeenough to shi t down the ree energy barrier to a value lowerthan those obtained or A (see Table 4). The improvemento the level o theory to a triple-zeta quality basis-set

(B3LYP/6-311+G(2d,p)/LanL2DZ//B3LYP/6-31G(d)/ LanL2DZ) decreases the energy barriers or all processesby 1 kcal mol-1 on average, keeping the same qualitativetrend. In aqueous solution the barriers are slightly higher(6-11%) compared to gas phase, except or Cys interaction,which value was 18.8 kcal mol-1 (0.5 kcal mol-1 lower thanin gas phase) at the B3LYP/6-31G(d)/LanL2DZ level.For the other processes the calculatedGa,aqbarriers were21.4 (G), 23.1 (A) and 19.4 (Met) at the B3LYP/6-31G(d)/ LanL2DZ level o theory. It is now interesting to re er to ourprevious papers on the kinetics o G27and amino acids (Cysand Met)28 binding to cisplatin. In re erence 28 the thermalcorrection accounted orca. 3% o ree energy barrier ingas phase, in close agreement with the estimative reportedhere or Cys and Met interactions. Nonetheless, in aqueoussolution the results were somewhat di erent, with solvente ect corresponding to an important contribution around30% o the activation Gibbs ree energy in re erence 28.These are likely attributed to the type o vector ligand and

to the chemical process investigated in re erence 28, wherethe chloride is the leaving group. Besides these theoreticaleatures, the predicted trend or cisplatin28was also di erentrom our present work, with Met barrier ound smaller

by 1.3 kcal mol-1 than Cys one at the very same level o theory used here. Experimentally, the average values orcisplatin reaction rom two experiments are 20.2 (Met) and20.4 kcal mol-1 (Cys).46-49 There ore, concerning the Cysand Met complexation, we can say that the reactions with[Pt(AHTC)Cl(H2O)]+ species are aster than with cisplatin,with the Cys complex being the kinetic product. In thereaction o G with cisplatin monoaqua species described

Table 4. Activation energies (kcal mol-1) and rate constant (mol-1 L s-1) calculated or AHTC-Pt aquated species binding processes to purine bases G andA and sul ur-containing amino acids Cys and Met. The k2 values shown were calculated in aqueous solution

Ga,gelenuc GTa,g dGasol v Ga a Ga,aq b 102 k2

c

GB3LYP/6-31G(d)/LanL2DZ 21.9 1.70 1.19 20.2 21.4 0.14B3LYP/6-311+G(2d,p)/LanL2DZd 21.2 - - 19.5 20.7 0.44AB3LYP/6-31G(d)/LanL2DZ 21.0 0.18 2.23 20.9 23.1 0.01B3LYP/6-311+G(2d,p)/LanL2DZd 19.6 - - 19.4 21.7 0.08MetB3LYP/6-31G(d)/LanL2DZ 18.6 0.39 1.25 18.2 19.4 3.55B3LYP/6-311+G(2d,p)/LanL2DZd 17.6 - - 17.2 18.5 17.64CysB3LYP/6-31G(d)/LanL2DZ 19.4 0.10 0.47 19.3 18.8 9.77B3LYP/6-311+G(2d,p)/LanL2DZd 18.2 - - 18.1 17.6 74.07aCalculated by equation 2.bCalculated by equation 3.cCalculated by equation 6.dThe thermal correction (GTa,g) and relative solvation energy (dGasolv)were obtained at the B3LYP/6-31G(d)/Lanl2DZ level o theory.

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in re erence 27, the contributions rom entropy and solventwere close to 9% and 3%, respectively, in accordancewith the results ound here. The calculated barrier or Gbinding to cisplatin was 20.9 kcal mol-1,27 which are only0.5 kcal mol-1 lower than the calculated value reported

in the present work or the hybrid complex with AHTCvector ligand. I we consider our highest level o theory(B3LYP/6-311+G(2d,p)/LanL2DZ//B3LYP/6-31G(d)/ LanL2DZ) the predicted value is 20.7 kcal mol-1, being0.2 kcal mol-1 lower than those ound or cisplatin. Theexperimental value or G binding spread over a range rom17.8 to 18.9 kcal mol-1, involving measurements with muchmore complex DNA matrix50,51 and then, are not directlycompared to the processes studied here. The G and Ainteractions with diaquated cisplatin was reported recentlyby Eriksson and co-workers44using DFT calculations at thesame level we applied in the present study. The calculatedactivation barriers in aqueous solution were 19.5 or Gand 24.0 kcal mol-1 or A, with the ormer ound in goodagreement with the experimental data used (18.3 kcal mol-1).These values are also close to ours (21.4 and 23.1 or G andA, respectively), despite the great di erence in the systemsand processes analyzed.

The transition state theory (TST) developed by Eyringhas been most used in chemical kinetics studies.52 Thisapproach can be summarized by equation 6, where kB is theBoltzmann constant, T the absolute temperature (298.15 Kin the present work), h the Planck constant andGa is theactivation ree energy or the reaction, calculated as inequations 2 and 3.

(6)

k2 is the second order rate constant, which is a unctiono temperature, calculated at standard concentration o co = 1 mol L-1. It is interesting to point out that the rateconstants are much more sensitive than the activation reeenergy, moreover a small fuctuation inGa value, around1 kcal mol-1 as ound in re erence 28, shall generate a

wide spread range or k2. The second order rate constantsor the processes studied here were calculated in aqueoussolution with values given in the last column o Table 4.TheGa,aqvalues (see equation 3) were used or calculationo rate constants. For reaction with G, k2 values were0.1-0.4 10-2 mol-1 L s-1, which are close to thosecalculated or the parent complex cisplatin in re erence 27,0.1-0.3 10-2 mol-1 L s-1. Experimental data or cisplatinshows values one order o magnitude higher, spreadingover a broad range o 0.8-5.4 10-1 mol-1 L s-1.50,51For theamino acids the processes are aster, with rate constants

ound equal to 9.8-74.1 10-2 mol-1 L s-1 or Cys and

3.6-17.6 10-2 mol-1 L s-1 or Met. These results di errom those calculated or cisplatin at the same leve

reported in re erence 28, 0.110-2 mol-1 L s-1 (Cys) and0.79 10-2 mol-1 L s-1, but are closer to the experimentaldata or the parent compound: 2.2-3.86 10-2 and

3.6-3.96 10-2 mol-1L s-1 or Cys and Met interactions,46-49 respectively. Finally, the kinetic study described in thepresent work shows that the AHTC-Pt ollows closer thstandard mechanism o action o cisplatin, with the samrate pro le as represented in Scheme 3, there ore this newcompounds may be assigned as a promising lead moleculein the synthesis o novel antitumor drugs. We are nowengaged in going beyond the simple models or DNAand proteins, including in the calculations the backboneo the biomolecules. This is an essential step in order tode nitively understand the hypothesis o the antitumoaction mode o tetracycline and its derivatives.

Conclusions

The interaction o AHTC-Pt complex with relevanbiological nucleophiles (guanine, adenine, cysteine andmethionine) were investigated by means o theoreticamethods based on DFT approach. These reactive processes

ollow the standard action mode o cisplatin analogue

Scheme 3. Standard action mode or cisplatin derivatives. The rst stepis the hydrolysis (interaction with H2O), ollowing by binding to DNAbases, represented here by guanine (G). The interaction with proteinsas indicated by the binding processes with Cys or Met, is also shownas a side process. (a) Processes or cisplatin parent compound. Thvalues correspond to the experimental rate constants (in mol-1 L s-1)collected rom literature. (b) Processes or AHTC-Pt derivative with 2 (in mol-1 L s-1) values obtained rom DFT calculations carried out in ourprevious paper (hydrolysis reaction only) and in the present work.

PtH3N

H3N Cl

ClPt

H3N

H3N Cl

OH2Pt

H3N

H3N Cl

G

H2O G

2.5-8.5x10-5 0.8-5.4x10-1

PtH3N

H3N Cl

Cys/Met

Cys/Met 2.2-3.9x10-2

O

O

NH2

Pt

Cl

ClH2O

0.5x10-5

O

O

NH2

Pt

Cl

OH2G

0.1x10-2

O

O

NH2

Pt

Cl

G

Cys/Met 3.6-9.8x10-2

O

O

NH2

Pt

Cl

Cys/Met

(a)

(b)

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comprising the activation hydrolysis step and bindingto DNA bases (G and A). The interaction with sul ur-containing amino acids also plays a primary role indetermining the bioavailability o the drug, there ore theunderstanding o the reaction mechanism at a molecular

level may assist in the design o new molecules withpotential biological response.The hydrolysis processes, leading to [Pt(AHTC)

Cl(H2O)]+ was studied in our previous paper given second-order rate constant (k2) equal to 0.510-5mol-1L s-1, which isclose to the value observed or the parent molecule cisplatin(2.5-8.5x10-5mol-1L s-1). The ollowing processes involvedthe aquated species, yielding the products [Pt(AHTC)Cl(Nu)]+ with Nu = G, A, Cys and Met. The structureso these molecules were described in addition to the1Hand 13C NMR spectra. The1H NMR was more sensitive,showing some ngerprints or A and G adducts. For thesespecies the substituent at position C6 o the purine baseswas ound to be in close contact with methyl groups atC4 o AHTC, splitting and shi ting down eld the signsassigned to the CH3 groups relative to the correspondingvalues or the ree ligand. Taking the average chemicalshi t or the three hydrogen atoms, we oundd at 2.8 ppm

or both CH3 groups in the ree AHTC ligand and theircomplexes with Cys and Met. Nonetheless, or A and Gtwo peaks are predicted at 2.8 and 3.3 ppm (A) and 3.2and 3.8 ppm (G).

The whole reaction pathway was tracked or eachprocess analyzed, with the kinetic properties calculatedwithin the supermolecule approach. In this methodology thereagents and products are treated as molecular complexes,where the structures are determined ollowing the intrinsicreaction coordinate starting orm the transition states (TS).The TS species play a key role on the activation barrier andcan not be assessed experimentally; there ore the theoreticaldescription given in the present study can be valuable orexperimentalists in planning molecules and processes withcontrolled reactivity. For reactions analyzed here the rateconstants were (102 k2 in mol-1 L s-1): 0.1 (G), 0.01 (A),

3.6 (Met) and 9.8 (Cys). These values are 103

times asterthan the hydrolysis process, which is in per ect accordancewith the expected behavior or standard cisplatin analogues.Comparing to experimental data or cisplatin, 8-5410-2 (G) and 2.2-3.910-2 mol-1 L s-1 (Cys and Met) we notedthat the reaction o AHTC-Pt derivative with G is almosttwo orders o magnitude slower and the interaction withCys or Met slightly aster. Indeed the values predicted orAHTC-Pt compare well with cisplatin, considering thedi erences in the coordination shells and, consequently,in the processes investigated. It is worth mentioning thatrate constant is a very sensitive quantity and then, the

values may change signi cantly with small fuctuation inthe activation ree energy.

Acknowledgments

The authors would like to thank the Brazilian AgenciesCNPq (Conselho Nacional de Desenvolvimento Cient coe Tecnolgico) and FAPEMIG (Fundao de Amparo Pesquisa do Estado de Minas Gerais) or inancialsupport. This work was partially supported by the projectsPRONEX-FAPEMIG/EDT-526/07.

Supplementary Information

Supplementary data are available ree o charge at http:// jbcs.sbq.org.br, as PDF le.

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Received: February 7, 2008

Web Release Date: September 3, 2008

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S u p p l em

en

t ar yI n

f or m

a t i on

J. Braz. Chem. Soc. , Vol. 19, No. 8, S1, 2008.Printed in Brazil - 2008 Sociedade Brasileira de Qumica

0103 - 5053 $6.00+0.00

*e-mail: [email protected]

Reactivity of 5a,6-Anhydrotetracycline Platinum(II) Complex with Biological Nucleophiles:A Theoretical Study

Bruna L. Marcial, a Luiz Antnio S. Costa, b Wagner B. De Almeida c and Hlio F. Dos Santos* ,a

a Ncleo de Estudos em Qumica Computacional, Departamento de Qumica, Universidade Federal de Juiz de Fora,36036-330 Juiz de Fora-MG, Brazil

b Escola Preparatria de Cadetes do Ar, Departamento de Ensino da Aeronutica, Comando da Aeronutica, Rua Santos Dumont, 149, 36205-970 Barbacena-MG, Brazil

c Laboratrio de Qumica Computacional e Modelagem Molecular, Departamento de Qumica,Universidade Federal de Minas Gerais, 31270-901 Belo Horizonte-MG, Brazil

Figure S1. B3LYP/6-31G(d)/LanL2DZ optimized geometries for the intermediates (I-1 and I-2) involved in the reaction path for formation of [Pt(AHTC)Cl(Nu)] + complexes, where Nu stands by A, G, Met and Cys, respectively. Values of the total energy are given in parenthesis (in a.u.).

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