trans-Platinum anticancer drug AMD443: A detailed theoretical study by DFT–TST method on the hydrolysis mechanism

Chemical Physics Letters 497 (2010) 142–148

Contents lists available at ScienceDirect

Chemical Physics Letters journal homepage: www.elsevier.com/locate/cplett

trans-Platinum anticancer drug AMD443: A detailed theoretical study by DFT–TST method on the hydrolysis mechanism Snehasis Banerjee a,c,*, Partha Sarathi Sengupta b, Asok K. Mukherjee c a

Department of Chemistry, Darjeeling Government College, Darjeeling 734101, India Department of Chemistry, Vivekananda Mahavidyalaya, Burdwan 713103, India c Department of Chemistry, The University of Burdwan, Golapbag, Burdwan 713104, India b

a r t i c l e

i n f o

Article history: Received 4 June 2010 In final form 28 July 2010 Available online 3 August 2010

a b s t r a c t The two-step hydrolysis of trans-[PtCl2(NH3)(2 picoline)], AMD443, a novel anticancer drug has been investigated using density functional theory (DFT) with and without a number of explicit solvent molecules. Pentacoordinated trigonal–bipyramidal (TBP)-like structure transition state (TS) along with other stationary points on potential energy surface were optimized and characterized. To obtain accurate energies for the reaction surfaces, single-point energies were calculated by conductor-like polarisable calculation model (CPCM) using larger basis sets. Significant differences in the geometry and position of the TBP transition state are found between explicitly solvated and gas phase structures. The computed values of rate constant of different steps are in good agreement with the available experimental results. Ó 2010 Elsevier B.V. All rights reserved.

1. Introduction Since the discovery of its anticancer activity, cisplatin (cis[PtCl2(NH3)2], cis-DDP) has become one of the most important clinical anticancer drugs [1]. Despite its success [2], cisplatin has some limitation including some serious dose-limiting side effects, inherent and acquired resistance and limited solubility in aqueous solution. Extensive effort has been devoted to the development of new cis-platinum compound that avoids such problems. In the continued search for novel cis-platinum anticancer drugs, the trans geometry of such drug molecules are of current interest [3]. The paradigm for structure–activity relationships of platinum complexes is that the trans-isomer of cisplatin, trans-DDP, and monodentate charged complexes are therapeutically inactive [4]. Contrary to these earlier findings, trans-platinum complexes have been demonstrated in the last two decades to be endowed with antitumor activity [3,5,6] and some them are under clinical trials [7]. Farrel et al. [8] reported that trans-platinum complexes with planar amine ligands have antitumor activity superior to transplatin especially in cisplatin resistant cell lines and the antitumor activity of trans complexes could be increased by using bulky carrier ligands which reduce the rate of replacement of the chloro ligands. Bulky ligands would limit axial access to the Pt atom and therefore inhibit the formation of the five coordinated intermediate. The presence of planar ligands in trans-[PtCl2(L)2] (L = pyridine * Corresponding author at: Department of Chemistry, Darjeeling Government College, Darjeeling 734101, India. E-mail address: [email protected] (S. Banerjee). 0009-2614/$ - see front matter Ó 2010 Elsevier B.V. All rights reserved. doi:10.1016/j.cplett.2010.07.088

or thiozole) and trans-[PtCl2(NH3)(L)] (L = quinoline) complexes greatly enhances the cytotoxicity of such species, with respect to their corresponding cis-isomer and also to transplatin [9]. The primary target of Pt(II) based drugs is genomic DNA, specifically the N7 atoms of the purine bases, guanine (G) and adenine (A). This point of attack first generates monofunctional adducts, which subsequently closes by coordination to N7 atom of another purine producing bifunctional adducts through intrastrand and interstrand cross-links (CLs). Cisplatin adducts in linear DNA include 90% 1,2-d(GpG) or d(ApG) CLs with other lesions including 1,3-d(GpNpG) intrastrand CLs and to a lesser extent interstrand cross-links (ICLs), monofunctional adducts and various DNA– protein CLs [10]. trans-Platinum complexes cannot form such intrastrand cross-links between adjacent purines for steric reasons, and consequently, they exhibit monofunctional adducts, 1,3-intrastrand CLs and ICLs [11] (Fig. 1). It is generally believed that the hydrolysis process is the key activation step inside the cell before the drug reaches its intracellular target DNA [12–14]. In regard to the mechanism of action of Pt-based anticancer drug, the theoretical and experimental investigation of the aquation of cisplatin and its analogues has become a topic of current interest [15–24]. We have reported [25] recently a detailed theoretical study of the mechanism of hydrolysis of the orally active anticancer drug ZD0473. The trans isomer of this drug, namely, AMD443 has been reported [26] to have similar anticancer activity (better than cisplatin). The experimental mechanistic study of hydrolysis of this drug has been reported fairly recently [27]. In the present paper we report the detailed theoretical study of this hydrolysis reaction by a combination of DFT and transition state theory (TST). The

S. Banerjee et al. / Chemical Physics Letters 497 (2010) 142–148

143

Fig. 1. Schemetic representation of the modes of DNA intra- and inter-strand cross-links by cisplatin and inter-strand cross-links by trans-[PtCl2(NH3)L] (L = NH3 or planar amine).

purpose is to understand the mechanism of the reaction in terms of variation of electronic charge distributions during the course of the reaction. To this end, the stepwise hydrolysis processes of AMD443 were explored by DFT method. Two different models were employed; in model 1 the trans-Pt complex and the attacking water molecule in each substitution reaction were considered (as shown in Scheme 1) and in model 2 geometry optimization and search for transition state have been attempted by considering three explicit water molecules (as shown in Scheme 2) to account more accurately for specific H-bond interactions and to provide a more accurate description of the hydration of the leaving chloride anion. In this model for the first aquation step, the four water molecules were placed in the reaction hemisphere of the trans[PtCl2(NH3)(2-picoline)] species. For the second aquation step, the first leaving chloride anion was removed and the water molecules were placed in the reaction hemisphere of the monoaquated trans-[PtCl(NH3)(2-picoline)(OH2)]+ cation. Energies, structures and thermodynamic properties were calculated, discussed and compared with available experimental results. Scheme 1: Reaction steps in trans-[PtCl2(NH3)(2-picoline)] hydrolysis (model 1)

trans-½PtCl2 ðNH3 Þð2-picolineÞ þ H2 O 

ð1aÞ



ð1bÞ

! trans-½PtClðNH3 Þð2-picolineÞðOH2 Þþ þ Cl trans-½PtClðNH3 Þð2-picolineÞðOH2 Þþ þ H2 O ! trans-½PtðNH3 Þð2-picolineÞðOH2 Þ2 2þ þ Cl

Scheme 2: Reaction steps according to model 2

trans-½PtCl2 ðNH3 Þð2-picolineÞðH2 OÞ4 

! trans-½PtClðNH3 Þð2-picolineÞðOH2 Þþ ðH2 OÞ3 þ Cl

ð2aÞ

trans-½PtClðNH3 Þð2-picolineÞðOH2 Þþ ðH2 OÞ4 2þ

further text. All stationary points located on the PES were characterized as minima or first order transition state through harmonic frequency calculations. For every TS the corresponding structures of the intermediates were confirmed by the intrinsic reaction coordinate (IRC) method [32,33]. Thermal contribution to the energetic properties was also considered at 298.15 K and 1 atm. To obtain accurate hydrolysis picture the same computational procedure was followed, using three explicit water molecules for solvation. Improved polarized continuum-model (CPCM) [34–37] singlepoint (SP) energy calculations were performed at B3LYP level with the larger basis set 6-31++G(2df,2pd) for all atoms except platinum. The platinum valence basis set was augmented by a set of diffuse (as = 0.0075, ap = 0.013, and ad = 0.025) and polarization (af = 1.419333, 0.466239, ag = 1.207702) functions [38] to create well-balanced basis set. This basis set combination is designated as BSII in further text. B3LYP/BSI level ‘gas phase’ thermal corrections were used in these calculations at room temperature (298.15 K). All the CPCM calculations were carried out using an average tesserea area of 0.2 Å2. In this study, UAKS cavities were used to evaluate the aqueous solvation effects using CPCM. The UAKS cavities use united atom topological model (UATM) [39] with radii optimized for PBE0/6-31G(d) [40,41]. Natural bond orbital (NBO) analysis [42,43] at B3LYP/BSI level was carried out to understand the orbital interactions and charge delocalization during the course of the reaction. The rate constants (k) were calculated within the transition state theory according to the Eyring equation [44]

kðTÞ ¼

kB T DGy e RT ; h

ð3Þ

where kB is the Boltzmann constant, T the absolute temperature and h the Planck constant. DG  is the activation free energy for each step. 3. Results and discussion



! trans-½PtðNH3 Þð2-picolineÞðOH2 Þ2  ðH2 OÞ3 þ Cl

ð2bÞ

2. Computational methods All geometries and energies presented in the this study are computed at the gradient corrected DFT level using the threeparameter fit of exchange and correlation functionals of Becke (B3LYP) [28] which includes the correlation functional of Lee, Yang, and Parr (LYP) [29] as implemented in the Gaussian program package [30]. For all structure optimizations, we have used the 631G(d,p) basis set for all atoms except platinum atom, which was described by the quasi-relativistic Stuttgart–Dresden pseudo potential [31]. This basis set combination is designated as BSI in

In this section, the computational results will be presented and discussed. The Cartesian coordinates of optimized geometries of all the relevant species in the hydrolysis process are shown in the Supplementary material (Tables S1 and S2). The calculated geometric parameters of AMD443 are compared with the experimental X-ray data [27] (Table 1). 3.1. Structural analysis The minimized structure of AMD443 matches the crystallographic data with bond distances within 0.06 Å and bond angles within 2° (Table 1) thus indicating that the choice of method and basis sets provide a good description of molecular structures of

144

S. Banerjee et al. / Chemical Physics Letters 497 (2010) 142–148

Table 1 Comparison between calculated and experimental geometrical parameters for AMD443. Parametera

Calculatedb

Experimentalc

Pt–Cl1 Pt–Cl2 Pt–N1 Pt–N2 H3CPt N1–Pt–N2 N1–Pt–Cl1 N1–Pt–Cl2 N2–Pt–Cl1 N2–Pt–Cl2 Cl1–Pt–Cl2 Cl1–Pt–N1–C3 Cl2–Pt–N1–C3

2.368 2.364 2.080 2.051 3.239 178.7 91.7 92.1 88.0 88.2 176.2 101.1 79.0

2.313(2) 2.307(2) 2.028(7) 2.037(8) 3.207 178.9(3) 90.1(2) 92.0(2) 89.6(2) 88.4(2) 177.4(8)

a

The bond length in Å and bond angle in degree. The geometrical parameters calculated at B3LYP/BSI level in this work. c The experimental values come from the X-ray structure of AMD443 from Ref. [27]. b

these systems. Based on such computed geometries, we can carry out further study on energies, thermodynamic and kinetic properties of the hydrolysis of AMD443 at a higher basis set level. All reactant and product complexes have nearly planar configuration around the central Pt atom. 3.1.1. Hydrolysis processes according to model 1 The fully optimized structures for the species involved in the hydrolysis of AMD443 according to model 1 are shown in Fig. S1 (Supporting material). The title second order nucleophilic substitution (SN2) reaction was characterized by an exchange of two ligands Cl and H2O. In the first reactant intermediate, trans-

[PtCl2(NH3)(2-picoline)]H2O, RI1, the entering water molecule which is 3.30 Å away from the central Pt atom renders squarepyramid-like structure to RI1 and is well oriented to initiate the reaction. The transition state (TS1) structure found for the first hydrolysis step is characterized by an imaginary frequency of 151 cm1 in which the PtClleaving bond is breaking and PtOentering bond is forming. The other Cl atom forms the equatorial plane of the TS structure. The distance PtClleaving increases from 2.37 Å in RI1 to 2.90 Å in TS1 while the distance PtOentering reduces from 3.30 Å in RI1 to 2.49 Å in TS1. Thus bond formation and bond breakage occurs simultaneously indicating a concerted reaction process. As a result of the small entering group (E)-metal (M)-leaving group (L) angle (\L–M–E  65°), the TS minimizes the repulsion between the metal ‘lone pairs’ and electron pairs of L and E ligands [45,46]. In the structure of the first product intermediate trans-[PtCl(NH3)(OH2)(2picoline)]+Cl, PI1, the Cl ion as ligand has been completely substituted by H2O which forms a bond with Pt at a distance of 3.99 Å and forms hydrogen bonds with neighboring water molecules at distances of 1.79 Å and 2.10 Å. In PI1, the Pt–Cl1 bond length decreases from 2.35 Å in TS1 to 2.32 Å in PI1. This can be attributed to the more stabilizing effect of the H2O (than Cl) ligand in trans position [27,47]. The monoaquated product P1 has an almost perfect square-planar geometry, with the leaving Cl ion completely expelled by H2O molecule. In the second hydrolysis step the intermediate trans-[PtCl (NH3)(H2O)(2-picoline)]+H2O, RI2, the entering water molecule forms a H-bond with the hydrogens of ammine group at a distance of 1.78 Å and the incoming water molecule is 3.62 Å away from Pt atom. In RI2 the breaking Pt–Cl bond length is 2.30 Å (which is 0.7 Å shorter than that in RI1) because of lower trans effect resulting from the stronger electron-donating properties of the transpositioned H2O than that of Cl ligand. This is reflected in their activation energies (Section 3.3). The transition state structure (TS2) is found to have an imaginary frequency of 161 cm1, in which the

Fig. 2. Geometries of the species involved in the hydrolysis of AMD443 calculated at B3LYP/BSI and main bond lengths (Å) and bond angles in model 2.

145

S. Banerjee et al. / Chemical Physics Letters 497 (2010) 142–148

forming PtOentering bond is 2.26 Å (2.49 Å in TS1) and the breaking Pt–Cl1 bond is 2.82 Å (2.90 Å in TS1). The relatively larger L–M–E angle (68°) and shorter metal–ligand bond highly destabilizes the transition state TS2 than TS1. In the optimized product intermediate trans-[Pt(NH3)(H2O)2(2-picoline)]2+Cl, PI2, the second chloride ligand has been completely substituted by a second H2O molecule which forms a bond with Pt at a distance of 1.99 Å. The leaving Cl ion forms strong H-bonds with the ammine group and the coordinated H2O molecule at distances of 2.29 Å and 1.36 Å, respectively. Again in TS1, PI1, TS2 and PI2, the leaving Cl ion is partially solvated by water molecules in the second coordination sphere. Interestingly in PI2, the H6 atom of coordinated H2O molecule (Fig. S1) is much closer to the leaving Cl ligand than the O atom of H2O molecule (ROwat2–H6 = 1.54 Å) resulting partial proton transferring between H2O and Cl ligands. The final product trans-diaqua complex P2 has again an almost perfect square-planar geometry with the Cl ion completely expelled by the second H2O molecule. 3.1.2. Hydrolysis processes according to model 2 The optimized structures (Fig. 2) of the stationary state in this model show that effect of the extra water molecules leads to a better H-bonded structure compared to the gas phase structure in model 1. In RI1, four water molecules form a tight interconnected Hbonds network. As compared to gas phase we note that the entering water molecule is a little further away from the metal center (3.48 Å compared to 3.30 Å in gas phase) due to its interaction with the extra water molecules. The transition state (TS1) structure found for the first hydrolysis step is characterized by an imaginary frequency of 134 cm1 in which the Pt–Cl2 bond is breaking and PtOentering bond is forming. The distance PtOentering decreases from 3.48 Å in RI1 to 2.43 Å in TS1 while the PtClleaving distance increases from 2.38 Å in RI1 to 2.83 Å in TS1. In PI1, leaving Cl ligand is 3.87 Å away from the central Pt atom. In this model the leaving Cl ion form more prominent H-bonds with the explicit water molecules at distances of 1.94 Å, 2.22 Å and 2.28 Å, respectively. In RI2, the three explicit water molecules and incoming water molecule form again a stable hydrogen bond network and the H2O molecule that enters is 3.74 Å away from Pt while the gas phase distance is 3.62 Å. In RI2 the breaking Pt–Cl bond length is 2.34 Å (which is 0.4 Å shorter than that in RI1). The transition state structure (TS2) is found to have an imaginary frequency of 129 cm1, in which the forming PtOwat2 bond is 2.34 (2.43 Å in TS1) and the breaking Pt–Cl1 bond is 2.74 Å (2.83 Å in TS1) with the L–M–E angle being 81.5° (69.3° in TS1). This data again support the destabilization of TS2 than TS1. In PI2, the leaving Cl ion attracts the positively charged protons of several water molecules and has moved to a distance of 3.70 Å from Pt center. In TS1, PI1, TS2 and PI2, the leaving Cl ion is partially solvated by water molecules in the second coordination sphere. In PI2 the leaving Cl ion forms three hydrogen bonds with the extra water molecules, the hydrogen bond lengths being 2.15 Å, 2.16 Å, 2.25 Å and 2.27 Å, respectively indicating a strong interaction. Variations of Pt–E and Pt–L bond length (collected from Fig. 2 and Fig. S1) during the hydrolysis via two models are displayed in Fig. S2. In both transition states (TS1 and TS2), the 2-picoline ligand being cis to the leaving chloride ligand becomes axial in the trigonal plane of the five coordinate TS and interacts with the entering and leaving groups at almost an angle of 90°. Such steric effect destabilizes the trigonal–bipyramidal transition states. 3.2. NBO analysis NBO analysis has provides detailed insight into the nature of electronic structure and bonding in the complexes involved in

the reaction. Table 2 summarizes the second order perturbative estimates of ‘donor–acceptor’ (bond–antibond) interactions in the NBO basis for selected stationary structures in explicit solvent model for the reaction under study. The calculated gas phase results are also summarized in Table S4 (Supplementary material). Some selected NBO orbitals were plotted in Fig. S3. In these interactions the lone pairs of oxygen (nO) or chlorine (nCl) atoms mainly act as donor orbital. Absence of any L ? Pt or E ? Pt interaction in the intermediate structures supports the fact that intermediate structures are not five-coordinated. In the TS structures electron donations from lone pairs of Cl- and O-donor are found as shown in Tables 2 and S4. According to the natural population analysis (NPA), the net charge of important atoms for every stationary point is listed in Table S5. In line with the geometric structural changes (Fig. S2), Table 2 Second order perturbation theory analysis calculated at B3LYP/BSI level of the Fock matrix for the species involved in model 2 of the reaction based on the NBO method. Donor (i) ? acceptor (j) First stepa RI1 n(2)O28 ? r*N3–H24 n(1)O28 ? r*O5–H7 n(2)O28 ? r*O5–H7 n(2)O31 ? r*O28–H30 n(3)Cl2 ? r*O31–H32 n(3)Cl4 ? r*O25–H26 TS1 n(4)Cl4 ? r*Pt1–Cl2 n(2)O5 ? r*Pt1–Cl2 n(3)Cl4 ? r*O25–H26 n(3)Cl4 ? r*O5–H6 n(4)Cl4 ? r*O5–H6 n(2)O28 ? r*O5–H7 n(2)O31 ? r*28–H30 n(1)O28 ? r*N3–H24 PI1 n(3)Cl4 ? r*N3–H23 n(4)Cl4 ? n*H6 n(2)Cl4 ? r*O25–H26 n(2)O28 ? r*O5–H7 n(2)O31 ? r*28–H30 Second stepa RI2 n(2)O27 ? n*H26 n(2)O5 ? n*H28 n(2)O30 ? r*N3–H24 n(2)O33 ? r*O5–H6 n(1)O30 ? r*O5–H7 n(3)Cl4 ? r*O33–H35 n(3)Cl4 ? r*O30–H32 TS2 n(4)Cl4 ? n*Pt1 n(2)O5 ? n*(6)Pt1 n(2)O5 ? n*(5)Pt1 n(2)O33 ? n*H6 n(3)Cl4 ? r*O30–H32 n(2)Cl4 ? r*O33–H35 n(2)O30 ? r*O3–H7 n(1)O30 ? r*N3–H24 n(2)O27 ? r*O2–H26 n(1)O27 ? r*N3–H22 PI2 n(2)Cl4 ? r*O33–H35 n(3)Cl4 ? r*N3–H23 n(3)Cl4 ? r*O30–H32 n(4)Cl4 ? r*O27–H29 n(1)O30 ? r*N3–H24 n(2)O27 ? r*O2–H26 n(2)O30 ? r*O3–H7 n(2)O33 ? r*O5–H6 Starred label (*) denotes antibonding. a n(i)A is valance lone pair orbital (i) on atom A.

Eij (kJ/mol)

50.1 38.4 18.1 120.1 62.2 40.8 100.8 92.2 14.9 41.4 21.4 70.2 104.1 40.4 56.1 289.8 48.8 93.8 88.0

280.7 240.7 60.2 81.0 40.3 18.4 21.2 117.1 98.2 48.8 160.6 68.5 62.1 60.8 40.4 109.6 20.5 66.9 40.6 48.3 66.3 18.7 233.6 131.7 183.2

146

S. Banerjee et al. / Chemical Physics Letters 497 (2010) 142–148

Table 3 Relative gas-phase, ZPE-corrected energies, enthalpies, free energies, solvation free energies (all in kJ mol1), entropies (Cal K1 mol1) and rate constant, k (in s1) calculated for intermediate species and transition state of the hydrolysis of the title complex. Model 1a

First aquation DE DEtot/ZPE Htherm Gtherm DH DG S DGsolv kf kr

Model 2a TS1

PI1

RI1

TS1

PI1

RI1

TS1

PI1

0 0 537.4 366.7 0 0 136.2

88.3 87.8 533.0 373.2 83.9 94.8 127.5

32.3 31.5 532.5 370.3 27.4 35.8 129.5

0 0 754.7 544.1 0 0 168.1

76.1 77.5 754.9 545.9 76.3 77.8 166.9

27.2 28.6 755.8 545.1 28.4 28.2 168.2

0 0

87.0 86.5

24.0 23.2

0 0

82.6 93.6

19.1 26.3

14.1

23.2 2.4  104 1.0

26.3

1.5  104 2.8  102

RI2 Second aquation DE 0 DEtot/ZPE 0 Htherm 603.7 Gtherm 432.7 DH 0 DG 0 S 136.5 DGsolv kf kr

1.4  101 1.2  104

c

Model 2a

2.6  105

Solutionb

Experimentc

TS2

PI2

RI2

TS2

PI2

RI2

TS2

PI2

134.3 133.5 599.3 438.8 129.8 140.3 128.1

89.4 82.2 593.9 428.3 79.7 85.1 132.2

0 0 825.8 620.5 0 0 163.9

126.2 125.4 824.5 620.0 124.9 125.7 163.3

43.6 45.5 824.6 627.1 42.5 50.1 157.7

0 0

116.4 115.6

81.2 73.9

0 0

112.0 122.5

79.3 86.6

126.8

151.4 2.1  109 3.1  106

137.7

1.6  1012 1.3  103

5.8  1010 3.5  101

2.7  106

BSI basis set used. B3LYP(CPCM)/BSII//B3LYP/BSI calculation. From Ref. [27].

125.4 115.6

117.6

Relative energy (ΔΕ tot/ZPE)/ kJmol

-1

120

first hydrolysis second hydrolysis

133.5

model 1 model 2 solution

126.4 87.8 82.2 86.5

80

73.9

77.5

99.5

28.6 second step

23.2

84.4

140

115.6

120 100 80 60

0.0

0.0

0

RI1

118.6

89.0 102.4 105.0 86.5

31.5 first step

101.2 89.4 99.5

117.1 120.1

45.5

40

145.6

TS1

PI1

RI2

TS2

PI2

Fig. 3. Calculated reaction ZPE-corrected energetic profiles of the first and second hydrolysis steps of AMD443 according to model 1, model 2 and in aqueous phase.

the most remarkable variations of charges also occur in the three atoms which directly relate to the reactions, i.e., the central Pt atom, the leaving Cl ion and the entering O atom as the reaction proceeds. The trend in the variation of charge can be clearly seen in Fig. S4. With the reaction proceeding, the net charge of the Cl ion as a leaving ligand becomes more negative, the positive charge of the central Pt atom first increases and then reduces because of receiving some negative charges as the TS approaches the product state. Thus there is a charge transfer among the related atoms, and that the negative charge gain of the Cl ion is greater than the negative charge loss of the Pt atom. To meet the charge conservation of the hydrolysis reaction, the negative charge of the O atom of the

tin pla tin s i c pla n rbo iplati ca in al x lat o 8 ap d 11 ne JM EP -D 73 cis 04 43 ZD D4 AM

Activation ene rgy (kJ/mol)

a

Experimentc

RI1

Model 1a

b

Solutionb

40 20 0

Fig. 4. Comparison between calculated activation energies for some Pt(II) complexes in neutral condition.

entering water ligand, decreases to favor the nucleophilic attack in the formation of a relatively stable intermediate complex. 3.3. Energy profiles The computed relative electronic energies, enthalpies and free energies of the stationary points in models 1 and 2 and in bulk

S. Banerjee et al. / Chemical Physics Letters 497 (2010) 142–148

solution (CPCM) along with their solvation energies, entropies and thermal correction at 298.15 K for the hydrolysis of the title complex is presented in Table 3. On the basis of these results, the computed ZPE-corrected energy profiles (DEtot/ZPE) are shown in Fig. 3. As expected, values of barrier heights are lower in the model 2 than in gas phase by an extent of 10.3 kJ/mol for the first hydrolysis step and 8.1 kJ/mol for the second step. The SP energies calculated using CPCM solvation model in aqueous solution are also indicated in Fig. 3 (blue). We can compare these barrier heights with the aquation of the related cis-complex (ZD0473) which we have reported recently [26]. Higher rate constants are observed for AMD443 for first aquation step and the back (anation) reaction. These trends are consistent with those noted previously in comparing the aquation of cis- and trans-Pt(II) ammine complexes (e.g. cisplatin and transplatin), where the faster rate of hydrolysis of trans dichloride complexes has been attributed to the different trans-labilizing abilities of the trans ligands in the substitution process (Cl > NH3) [28,48]. Again, the second aquation step for our complex is very slow (similar to second hydrolysis of transplatin [47]), which may be attributed to the stabilizing effect of the H2O ligand. This is consistent with the available experimental observations [27] for the three complexes, trans-[PtCl2(NH3)(n-picoline)] (n = 2, 3 or 4) for which no formation of the diaqua complex was observed at 277 K; only a small amount of the diaqua species formed for the 2-picoline complex (AMD443) at 310 K. The sequence of barrier heights as in Fig. 3 can also be seen in the profiles of DEtot and DG° (Fig. S5a and b). As the second hydrolysis step is rate-determining, the monoaquated product is the main species before entering the cell nucleus and interacting with the DNA target. This is similar to the hydrolysis of cisplatin [15], cis-DEP [21] and ZD0473 [25] but different from those of oxaliplatin [16], carboplatin [17], nedaplatin [18] and JM118 [20] in neutral medium. Calculated activation energies for these complexes in neutral conditions were compared with our results in Fig. 4. Both the steps are endothermic by 31.5 and 82.2 kJ/mol, respectively, in model 1 relative to their model 2 values 28.6 and 45.5 kJ/ mol, respectively. The reduced endothermicity in model 2 relative to model 1 is due to the inclusion of extra water molecules, i.e., an explicit solvent effect. For the first step the forward rate constant (kf) computed in aqueous solution by CPCM solvent model is 24  105 s1 in accordance with the experimental value 2.6  105 s1 and the calculated equilibrium constant (K = 2.4  104) by CPCM is almost in agreement with experimental value K = 3.9  105 at 277 K. The calculated equilibrium constant is 1.1  105 according to model 2.

4. Conclusion In this work, we have performed a complete mechanistic study of the hydrolysis processes of the sterically hindered novel anticancer drug AMD443, trans-[PtCl2(NH3)(2-picoline)] by DFT using two different models. Geometric structure and vibrational frequency were calculated at the B3LYP/BSI level in the gas phase followed by SP calculations at the B3LYP/BSII level of theory for the bulk solvation effect using CPCM model. Substitution proceeds via a pentacoordinated TBP transition state with a small angle between entering and leaving ligand (\L–M–E) indicating a concerted SN2 mechanism. For the first hydrolysis step, the complex AMD443 has a faster rate than that its cis isomer ZD0473 and for the second hydrolysis step, remarkable slower rate (kf = 2.1  109 s1) was found for the title complex. The reactions follow similar mechanism studied theoretically [19,48] for ligand substitution exchange of Pt(II) complexes. Three explicit water molecules were included in the calculation to improve the solvation energies and the results of calculation reveal that the non-bonded water molecules are

147

important to solvate the leaving chloride ligand and thus this model provides a more accurate description of the stabilization of the leaving group. Significant differences in the geometry and position of the TBP transition state are found between explicitly solvated and gas phase structures. The importance of the present work is that the difference in hydrolysis rates between the isomeric drugs AMD443 (trans-) and ZD0473 (cis-) is of clinical importance since such differences have direct effect on anticancer activity and cytotoxicity. Acknowledgments S. Banerjee thanks the UGC, Eastern Regional Office for granting a minor research project No. F. PSW-117/09-10 (ERO). We are grateful to Professor J.V. Burda for his kind help. We are also thankful to Dr. Juliana Fedoce Lopes for her helpful suggestions. Appendix A. Supplementary material Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.cplett.2010.07.088. References [1] B. Rosenberg, L. Camp, T. Krigas, Nature (Lond.) 205 (1965) 698. [2] S.E. Sherman, S. Lippard, J. Chem. Rev. 99 (1987) 1153. [3] G. Natile, M. Coluccia, in: A. Sigel, H. Sigel (Eds.), Metal Ions in Biological Systems, vol. 42, Marcel Dekker Inc., New York, 2004, pp. 209–250. [4] N. Farell, Transition Metal Complexes as Drugs and Chemotherapeutic Agent, Kluwer, Dordrecht, The Netherlands, 1989. [5] U. Bierbach, Y. Qu, T.W. Hambley, J. Peroutka, H.L. Nguyen, M. Doedee, N. Farrell, Inorg. Chem. 38 (1999) 3535. [6] G. Natile, M. Coluccia, Coord. Chem. Rev. 216 (2001) 383. [7] T. Servidei, C. Ferlini, A. Riccardi, D. Meco, G. Scambia, G. Segni, C. Manzottic, R. Riccardi, Eur. J. Cancer 37 (2001) 930. [8] N. Farrell, T.T.B. Ha, J.-P. Souchard, F.L. Wimmer, S. Cros, N.P. Johnson, J. Med. Chem. 32 (1989) 2240. [9] M. van Beusichem, N. Farrell, Inorg. Chem. 31 (1992) 634. [10] B. Lippert (Ed.), Cisplatin: Chemistry and Biochemistry of a Leading Anticancer Drug, Wiley-VCH, Zurich, 1999. [11] A. Eastman, M.M. Jennerwein, D.L. Nagel, Chem. Biol. Interact. 67 (1988) 7180. [12] F. Legendre, V. Bas, J. Kozelka, J.-C. Chottard, Chem.Eur.J 6 (2000) 2002. [13] S.E. Miller, D.A. House, Inorg. Chim. Acta 166 (1989) 189. [14] S.E. Miller, K.J. Gerard, D.A. House, Inorg. Chim. Acta 190 (1991) 135. [15] J. Raber, C. Zhu, L.A. Ericsson, Mol. Phys. 102 (2004) 2537. [16] M.F. Lucas, M. Pavelka, M.E. Alberto, N. Russo, J. Phys. Chem. B 113 (2009) 831. [17] M. Pavelka, M.F. Lucas, N. Russo, Chem. Eur. J. 13 (2007) 10108. [18] M.E. Alberto, M.F. Lucas, M. Pavelka, N. Russo, J. Phys. Chem. B 113 (2009) 14473. [19] Z. Chval, M. Sip, J. Mol. Struct. (THEOCHEM) 532 (2000) 59. [20] J. Raber, C. Zhu, L.A. Ericsson, J. Phys. Chem. B 109 (2005) 12195. [21] L.A.S. Costa, W.R. Rocha, Chem. Phys. 118 (2003) 10584. [22] J.K.-C. Lau, D.V. Deubel, J. Chem. Theory Comput. 2 (2006) 103. [23] J. Kozelka, Inorg. Chim. Acta 362 (2009) 651. [24] F. Arnesano, G. Natile, Coord. Chem. Rev. 253 (2009) 2070. [25] S. Banerjee, P.S. Sengupta, A.K. Mukherjee, Chem. Phys. Lett. 487 (2010) 108. [26] G. McGowan, S. Parsons, P.J. Sadler, Chem. Eur. J. 11 (2005) 4396. [27] G. McGowan, S. Parsons, P.J. Sadler, Inorg. Chem. 44 (2005) 7459. [28] A.D. Becke, J. Chem. Phys. 98 (1993) 5648. [29] C. Lee, W. Yang, R.G. Parr, Phys. Rev. B 37 (1988) 785. [30] M.J. Frisch et al., GAUSSIAN 03, Revision D.01, Gaussian, Inc., Wallingford, CT, 2004. [31] P. Schwerdtfeger, M. Dolg, W.H.E. Schwarz, G.A. Bowmaker, P.D.W. Boyd, J. Chem. Phys. 91 (1989) 1762 C. [32] C. Gonzalez, H.B. Schlegel, J. Phys. Chem. 94 (1990) 5523. [33] C. Gonzalez, H.B. Schlegel, J. Chem. Phys. 90 (1989) 2154. [34] V. Barone, M. Cossi, J. Phys. Chem. A 102 (1998) 1995. [35] M. Cossi, N. Rega, G. Scalmani, V. Barone, J. Comput. Chem. 24 (2003) 669. [36] A. Klamt, G. Schüürmann, J. Chem. Soc., Perkin Trans. 2 (1993) 799. [37] J. Andzelm, C. Kölmel, A. Klamt, J. Chem. Phys. 103 (1995) 9312. [38] J.V. Burda, M. Zeizinger, J. Sponer, J. Leszczynski, J. Chem. Phys. 113 (2000) 2224. [39] A. Ben-Naim, Y. Marcus, J. Chem. Phys. 81 (1984) 2016. [40] A.D. Mclean, G.S. Chandler, J. Chem. Phys. 72 (1980) 5639. [41] R. Krishnan, J.S. Binkley, R. Seeger, J.A. Pople, J. Chem. Phys. 72 (1980) 650. [42] A.E. Reed, L.A. Curtiss, F. Weinhold, Chem. Rev. 88 (1988) 899. [43] E.D. Glendening, A.E. Reed, J.E. Carpenter, F. Weinhold, NBO 3.0 Theoretical Chemistry Institute, University of Wisconsin, Madison, 1990.

148

S. Banerjee et al. / Chemical Physics Letters 497 (2010) 142–148

[44] K.A. Conors, Chemical Kinetics – The Study of Reaction Rate in Solution, Wiley, New York, 1990. p. 200. [45] Z. Lin, M.B. Hall, Inorg. Chem. 30 (1991) 646. [46] R.J. Deeth, L.I. Elding, Inorg. Chem. 35 (1996) 5019.

[47] B. Lippert, in: A. Sigel, H. Sigel (Eds.), Metal Ions in Biological Systems, vol. 33, Marcel Dekker Inc., New York, 1996, pp. 105–141. [48] S. Banerjee, P.S. Sengupta, A.K. Mukherjee, J. Mol. Struct. (THEOCHEM) 913 (2009) 97.