Kinetics and thermochemistry of hydrolysis mechanism of a novel anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)]: A DFT study

Accepted Manuscript Title: Kinetics and thermochemistry of hydrolysis mechanism of a novel anticancer agent trans-[PtCl2 (dimethylamine)(isopropylamine)]: A DFT study Author: Iftikar Hussain N.K. Gour Ramesh Ch. Deka PII: DOI: Reference:

S0009-2614(16)30150-6 http://dx.doi.org/doi:10.1016/j.cplett.2016.03.041 CPLETT 33727

To appear in: Received date: Revised date: Accepted date:

18-2-2016 15-3-2016 16-3-2016

Please cite this article as: I. Hussain, N.K. Gour, R.Ch. Deka, Kinetics and thermochemistry of hydrolysis mechanism of a novel anticancer agent trans[PtCl2 (dimethylamine)(isopropylamine)]: A DFT study, Chem. Phys. Lett. (2016), http://dx.doi.org/10.1016/j.cplett.2016.03.041 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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Highlights

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1. Hydrolysis mechanism of a novel transplain anticancer agent for anticancer activity

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2. First hydrolysis step is faster compared to the second step hydrolysis step

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3. The structure of transition state structure implies a concerted SN2 mechanism

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Kinetics and thermochemistry of hydrolysis mechanism of a novel anticancer agent

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trans-[PtCl2(dimethylamine)(isopropylamine)]: A DFT study

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Iftikar Hussain, N. K. Gour and Ramesh Ch. Deka*

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Department of Chemical Sciences, Tezpur University, Napaam, Tezpur -784028, Assam,

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India

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E-mail address: [email protected], Telephone: +91-9435380221

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Abstract

Theoretical investigation has been made on the hydrolysis mechanism of a novel

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transplatin anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)] in gas as well as

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aqueous phases using DFT method.

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stationary points on potential energy surface are optimized and characterized. The calculated

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activation barrier and the predicted relative free energies for the two successive steps are in

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good agreement with the experimental data reported in the literature. The rate constant are

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calculated using Eyring equation and results show that the second step is the rate-limiting

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process having higher activation energy compared to that of the first step.

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Keywords: DFT, trans-[PtCl2(dimethylamine)(isopropylamine)], Hydrolysis, IRC,

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The transition state geometries along with other

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Introduction The awareness of platinum-based antitumor drugs has its origin in 1960s, with the

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serendipitous Rosenberg’s discovery of cell inhibition by Pt electrodes.1-2 Cisplatin (cis-

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[PtCl2(NH3)2], cis-DDP is one of the most extensively used anticancer drugs and is effective

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against ovarian, testicular, head and neck malignancies.3-4 However, this antitumor agent

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exhibits some important dose-limiting toxicities, mainly nephrotoxicity, neurotoxicity, and

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ototoxicity.5-6 There is not a single platinum based drug which is efficient against all cancer

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types and some cancer cells are also found to be inherently resistant to such clinically

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approved platinum chemotherapeutic agents.

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resistance over time by the process of somatic evolution.7 In order to circumvent these

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issues, in the last thirty years, many investigations have been directed towards platinum

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based compounds endowed with higher anticancer activity and lower toxic effects than cis-

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DDP. In this search of novel cis-platin anticancer agents, certain trans-platin analogues are

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showing higher activity both in vitro and in vivo compared to their parent cis-isomers.8

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In addition, cancer cells can also acquire

Most of the structure/activity paradigm emerged from the initial studies by Cleare9-10

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and Hoeschele10 have now been interrogated. It has been believed that the trans-analogues of

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cisplatin and monodentate charged complexes are therapeutically inactive.11

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development of new highly active platinum based drugs do not coincide with the classical

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structure-activity rules; indicating the need for a re-evaluation of these rules. It has been

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notice that there are certain transplatin complexes which are showing higher antitumor

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activity both in vitro as well as in vivo.12-13

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complexes are gaining much interest in the field of anticancer drug discovery.14

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The recent

Thus, in the recent years these types of

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Farrel et al.15 for the first time reported that there are certain transplatin complexes

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having planner amino ligands showing activity superior to cisplatin, especially in case of

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cisplatin resistant cell lines. The activity of such complexes could be increased by using

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bulky carrier ligands which reduces the rate of replacement of the chloro ligands. The bulky

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ligand would limit the axial access of the Pt-atom thereby inhibit the formation of five

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coordinated intermediate.16 Examples of these antitumor trans-platinum complexes are the

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analogues of transplatin in which one ammine group is replaced by ligands such as thiazole,

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piperidine, piperazine, 4-picoline and cyclohexylamine; the analogs with branched

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asymmetric aliphatic amines.17 3

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It has been well established that the hydrolysis is the key activation step before

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reacting with its intercellular target DNA inside the cell.18-20 Thus, considerable attention has

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been paid in recent years to perform experimental and theoretical studies on the hydrolysis of

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the platinum based complexes.21-28 The cellular target of platinum based anticancer drugs are

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N7 atom of the purine bases i.e. guanine (G) and adenine (A) in the cellular DNA. It will

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first produce monofunctional adduct, which subsequently coordinates to N7 atom of another

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purine base generating bifunctional adducts through intrastrand and interstrand cross-links

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(CLs). Cisplatin adducts in linear DNA include 90% 1,2-d(GpG) or d(ApG) CLs with other

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lesions including 1,3-d(GpNpG) intrastrand CLs and to a lesser extent interstrand cross-links

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(ICLs), monofunctional adducts and various DNA protein CLs.29 However, transplatinum

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complexes cannot form such intrastrand cross-links instead it will exhibit only

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monofunctional adducts, 1,3-intrastrand CLs and ICLs.30 Thus, they will form a kinetically

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stable Pt-DNA adduct which is generally responsible for biologically activity of such

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complexes.31

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The first representative of this novel class of trans-platinum complexes is trans-

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[PtCl2(dimethylamine)(isopropylamine)], represented in Figure 1.

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mixture of aliphatic amines, showing marked activity against cis-DDP resistance in Pam212-

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ras tumor cells and can induce cell death through apoptosis.32 It was initially characterized

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by elemental analysis, mass spectrum, IR and NMR spectroscopic techniques.33

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hydrolysis mechanism of this complex is studied here, which is characterized by an exchange

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of two ligands (the chlorine anion and the water molecule) and it belongs to the class of

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second-order nucleophilic substitution (SN2) reactions.

The compound is a

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In this manuscript computational studies have been performed to explore the kinetics

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and mechanistic hydrolysis pathways of the novel transplain anticancer agent trans-

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[PtCl2(dimethylamine)(isopropylamine)] according to the Scheme 1. Since, experimental

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studies can only provide the total rate constant values, it is quite inadequate in predicting the

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mechanism as well as the thermochemistry of a given reaction. Therefore, in order to get the

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detailed insight into mechanism, kinetics as well as thermochemistry, we must rely on the

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quantum chemical methods. To the best of our knowledge, this is the first theoretical report

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exploring the two step hydrolysis mechanism of this complex.

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Computational Details 4

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Geometry optimization of the species involved in the two step hydrolysis mechanism

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of a novel transplain anticancer agent trans-[PtCl2(dimethylamine)(isopropylamine)] are

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made at density functional B3LYP34-35 level of theory. During geometry optimization, 6-

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311G(d,p) basis set36 was used for all elements except Pt. Considering the strong relativistic

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effect of Pt-atom, we have employed Los Alamos LanL2DZ basis set with effective core

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potential37 for platinum atom only. In order to determine the nature of different stationary

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points on the potential energy surface (PES), vibrational frequencies calculations are

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performed using the same level of theory at which the optimization are made. To obtained

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accurate hydrolysis picture of the complex, computational procedure are followed using

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aqueous phase polarized continuum-model (CPCM) also.38-39 This model is based upon the

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idea of generating multiple overlapping spheres for each atom within the molecule inside a

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dielectric continuum. The PCM model calculates the free energy of solvation by attempting

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to sum over three different terms i.e. Gelectrostatic, Gdispersion-repulsion, Gcavitation. The cavity used in

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the PCM is generated by a series of overlapping spheres normally defined by the van der

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Waals radii of the individual atoms, but, there is no specific way to define the radii of the

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spheres, however, in Gaussian it is possible to customize the spherical radii.

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In this investigation, we have considered minimal number of essential water molecule

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(only one explicit water molecule in our case) to reproduce the main features involved in the

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hydrolysis mechanism.40 The prime objective of this study is to concentrate mainly on the

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hydrolysis process. Since, only one water molecule at a time is being utilized for the

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hydrolysis pathway, replacing the Cl‾ ion, we have used a single water solvent molecule for

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this study. Considering more water molecules into the system is not going to affect the

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overall mechanism of the hydrolysis.41

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All the stationary point has been characterized with real and positive values of

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vibrational frequency, corresponding to stable minima except for the transition state

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structure.

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(NIMAG=1) referring the first order saddle point on the PES. Intrinsic reaction coordinate

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(IRC)42 calculations has also been performed to ascertain the minimum energy pathways

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(MEP) linking the reactant and product through the transition state on the potential energy

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surface. The minimum energy path (MEP) is obtained by intrinsic reaction coordinate (IRC)

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calculation performed using Gonzales-Schelgel steepest descent path in mass-weighted

The transition state has been characterized by only one imaginary frequency

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Cartesian with a gradient step-size of 0.01 (amu)1/2–bohr. All the electronic calculations are

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performed using GAUSSIAN 09 program package.43

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Results and Discussion The calculated enthalpy of reaction (ΔrH0), reaction free energies (ΔrG0) and Gibbs

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free energy of activation (ΔG#) at 298 K for the reaction channels involved in the hydrolysis

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process are recorded in Table 1. Free energy value (ΔrG0) and enthalpy of reaction (ΔrH0)

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show that both reaction channels are endothermic. From Table1, it can be clearly visible that

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the second step hydrolysis is more endothermic compared to the first step for both in gas as

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well as aqueous phase by a extent of 11.85 kJ mol-1 and 13.69 kJ mol-1, respectively. Thus,

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from the thermodynamic point of view, the first hydrolysis process may be more favorable

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compared to the second process.

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The optimized geometries along with the structural parameters obtained at DFT

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(B3LYP)/6-311G(d,p)/LanL2DZ level for reactant (R1 and R2), TS1, intermediate (IM1and

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IM2), TS2 and Product (P1 and P2) involved in the two steps hydrolysis mechanism of the

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title complex are shown in Figure 2. The second order nucleophilic substitution (SN2)

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hydrolysis of trans [PtCl2(dimethylamine)(isopropylamine)] is characterized by replacing

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two Cl‾ ion and followed by the addition of H2O molecule. In the first hydrolysis process,

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one of trans Cl‾ ion in the complex is replaced by H2O, forming the first reaction

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intermediate (IM1). In the gas phase transition states (TS1), the most important structural

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changes that have been observed are the breaking of Pt–Cl bond (leaving Cl‾ ion) and

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formation of the new bond Pt–O (entering H2O molecule). From Figure 2, in the gas phase,

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the distance of breaking Pt–Cl bond increases from 2.39 Å in R1 to 2.93 Å in TS1 (almost

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23% increase) whereas Pt–O bond distance is observed at 2.49Å in TS1. At the same time,

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one of the H-atom of the H2O molecule is also coordinating with the leaving Cl‾ ion at a

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distance 2.07 Å in TS1. In the first intermediate (IM1), one trans Cl‾ ion of the complex is

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completely replaced by H2O molecule (twice). The newly formed Pt–O bond decreases from

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2.49 Å in TS1 to 2.04 Å in IM1 (almost 18% decreases). This can be attributed to the more

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stabilized effect of H2O (than Cl‾) ligand in trans position.44-45 The intermediate has an

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almost perfect square planar geometry, with leaving Cl‾ ion completely replaced by H2O

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molecule and formed Pt–OH bond.

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intermediate is further replaced by H2O. During second step, the length of breaking Pt–Cl

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In the second hydrolysis process, other Cl‾ ion of

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bond is increased from 2.36 Å in IM1 to 2.96 Å in TS2 (almost 25% increase) whereas Pt–O

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comes close to 2.58 Å in TS2. The newly formed Pt–O bond decreases from 2.58 Å in TS2

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to 2.06 Å in P1 (almost 20% decreases). In this step, the H-atom of H2O is also forming a

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partial bond with the leaving Cl‾ ion at distance 2.03 Å in TS2. In order to obtained accurate hydrolysis mechanism, the same computational

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procedure is followed using aqueous phase polarized continuum-model (CPCM). In aqueous

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phase, the length of the breaking Pt–Cl bond increases from 2.40 Å in IM2 to 2.97 Å in TS1

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(almost 24% increase) whereas Pt–O is coming close to 2.64 Å in TS1. The newly formed

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Pt–O bond decreases from 2.64 Å in TS1 to 2.03 Å in IM2 (almost 23% decreases). In TS1,

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the H-atom of the H2O molecule is coordinating with the leaving Cl‾ ion at a distance 2.17 Å.

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In the further hydrolysis process, other Cl‾ ion is again replaced by H2O molecule. This

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process is featured by the increase in the Pt–Cl bond form 2.44 Å in IM2 to 3.94 Å in TS2

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(almost 61% increase), simultaneously, with a decrease in Pt-O bond from 2.15 Å in TS2 to

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2.06 Å in P2 (almost 4% decreases). Here the H atom of H2O is forming a partial bond with

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the leaving Cl‾ ion at distance 1.85 Å in TS2.

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The results obtained from the frequency calculations for the species involved in the

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hydrolysis of the title complex are recorded (Supplementary data, Table S1). It has been

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observed from the frequency calculations that all the species corresponds to the stable

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minima, having real positive vibrational frequencies on their potential energy surface, except

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in case of transition state structure. The transition states (TS1 and TS2) are characterized by

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only one imaginary frequency observed at 155i cm−1 and 169i cm−1 in case of gas phase

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calculations and 142i cm−1 and 45i cm−1 for the TS1 and TS2 in aqueous phase, respectively.

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Visualization of the imaginary frequency revealed a qualitative confirmation of the existence

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of transition states connecting reactants and products. Intrinsic reaction path calculations

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(IRC)7 have also been performed for each transition state under same level of theory. The

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result shows that each transition state smoothly connects the reactant and the product sides.

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Relative energies (including zero-point correction) for each of the species are determined

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with respect R+H2O and IM+H2O and the results are presented in Table 2. A potential

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energy diagrams of two step hydrolysis mechanism are constructed with the results obtained

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at the B3LYP/6-311G(d,p)/Lanl2DZ level and are shown in Figure 3. The relative energies

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calculated using CPCM solvation model in aqueous solution are also indicated in Figure 3

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(red). In the construction of energy diagram, zero-point energy corrected data as recorded in

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Table 2 are utilized. These energies are plotted with respect to the ground state energy of

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R+H2O and IM+H2O, including ZPE, which are arbitrarily taken as zero. The barrier height

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for the first step (TS1) in gas and in the aqueous phase are found to be 52.13 kJ mol-1 and

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52.71 kJ mol-1, respectively. For TS2, these barrier heights are found to be 55.91 kJ mol-1

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and 84.55 kJ mol-1 for gas phase and aqueous phase, respectively. A similar trend has also

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been observed in most of the platinum bases drugs, so our results are in consistent with the

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available data.45-47, 18 Form the ongoing discussion it is clear that the second step hydrolysis

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is rate-limiting process, which may be due to the stabilizing effect of the entering H2O

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ligands.48

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The rate constants (k) for two steps hydrolysis 2nd order reaction are calculated with

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the help of transition state theory. The rate constant expression is given by according to

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Eyring equation49

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where, k B

k T  RT e k (T )  B 194 (1) h is the Boltzmann constant, T is the absolute temperature and h is the

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G 

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Planck constant. ΔG# is the activation free energy for each step. The rate constant values for the first and second hydrolysis process are computed with

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the help of the above expression. The values of the rate constant, in gas phase are found to

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be 3.67 × 10-4 s-1 and 1.22 × 10-4 s-1 for the TS1 and TS2, respectively. Whereas, these

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values in aqueous phase are 5.44 × 10-4 s-1 and 2.65× 10-10 s-1, respectively. It is clear from

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the rate constant expressions that first hydrolysis process is somewhat faster compared to that

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of the second hydrolysis process. These values of rate constant are also in good agreement

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with the values observed in case of similar types of complexes.49-50

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Conclusions

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In the present manuscript, we have presented a systematic theoretical investigation on

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the

hydrolysis

mechanism

of

the

novel

anticancer

agent

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[PtCl2(dimethylamine)(isopropylamine) using DFT. All the structures are optimized along

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with the vibrational frequency calculations at B3LYP/6-311G(d,p)/Lanl2Dz level of theory in

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the gas phase as well as in aqueous phase using CPCM model. The hydrolysis is proceeded

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via a pentacoordinated trigonal bipyramidal (TBP) transition state structure implying a

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concerted SN2 mechanism. The structures of the transition states (TS1 and TS2) involved in

trans-

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the reaction path are confirmed by using IRC calculations. The activation barrier heights for

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two step hydrolysis reaction are found to be 52.13 kJ mol-1 and 55.91 kJ mol-1 (52.71 kJ mol-

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1

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Hence, the first hydrolysis step has found to be faster compared to the second step, indicating

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the monoaquo species of the complex is the most preferable species that react with the

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cellular DNA in vivo. Form the rate constant studies, it has also been found that the rate

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constant values for the first step is faster by an extent of 2.45 × 10-4 s-1 and 5.43 × 10-4 s-1 in

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gas phase and aqueous medium, respectively, compared to the second hydrolysis step in each

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case.

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investigation of the reaction mechanism of formation of hydrolyzed complex with its

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intercellular target DNA. These significantly different rates of the complex are of clinically

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importance since such difference have unambiguous effect on their anticancer property as

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well as cytotoxicity.

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Acknowledgements

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and 84.55 kJ mol-1 for aqueous phase) for the first and second transition state, respectively.

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The work presented in the manuscript will be very much useful for the further

The authors acknowledge financial support from the Department of Science and

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Technology, New Delhi in the form of a project (SR/NM.NS-1023/2011(G)). IH thanks

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University Grants Commission for providing the “Maulana Azad National Fellowship” F1-

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17.1/2013-14/MANF-2013-14-MUS-ASS-25447.

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Delhi for providing Dr D. S. K. Post doctoral fellowship.

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NKG also thankful to the UGC, New

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vol. 42, Marcel Dekker Inc., New York, 2004, pp. 209–250. 15. N. Farrell, T.T.B. Ha, J.P. Souchard, F.L. Wimmer, S. Cros, N.P. Johnson, J. Med. Chem.

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28. M.F. Lucas, M. Pavelka, M.E. Alberto, N. Russo, J. Phys. Chem. B 113 (2009) 831. 29. B. Lippert (Ed.), Cisplatin: chemistry and biochemistry of a leading anticancer drug, Wiley-VCH, Zurich, 1999. 30. A. Eastman, M.M. Jennerwein, D.L. Nagel, Chem. Biol. Interact. 67 (1988) 7180.

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33. J.M. Pérez, E.I. Montero, A.M. González, X. Solans, M. Font-Bardia, M.A. Fuertes, C.

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Alonso, C.N. Ranninger, J. Med. Chem. 43 (2000) 2411. 34. K. Kim, K. D. Jordan, J. Phys. Chem. 98 (1994) 10089.

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42. C. Gonzalez, H.B. Schlegel, J. Chem. Phys. 90 (1989) 2154. 43. M.J. Frisch et al. Gaussian 09, Revision B.01, Gaussian, Inc., Wallingford, CT, 2010.

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44. G. McGowan, S. Parsons, P.J. Sadler, Inorg. Chem. 44 (2005) 7459. 45. B. Lippert, in: A. Sigel, H. Sigel (Eds.), Metal Ions in Biological Systems, vol. 33, Marcel Dekker Inc., New York, 1996, pp. 105–141. 46. G. McGowan, S. Parsons, P.J. Sadler, Chem. Eur. J. 11 (2005) 4396. 47. M.E. Alberto, V. Butera, N. Russo, Inorg. Chem. 50 (2011) 6965 48. G. McGowan, S. Parsons, P.J. Sadler, Inorg. Chem. 44 (2005) 7459. 49. K.A. Conors, Chemical Kinetics – The Study of Reaction Rate in Solution, Wiley,New York, 1990, pp. 200. 50. M.E. Alberto, N. Russo, Chem. Commun. 47 (2011) 887.

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Table 1 Thermochemical data (kJ mol-1) for two steps hydrolysis reaction calculated at DFT

ΔrG(298)

ΔG#

R+H2O →IM+HCl

83.73

85.93

92.71

IM+H2O→P+HCl

95.05

97.78

R+H2O →IM+HCl

93.52

96.48

91.73

IM+H2O→P+HCl

108.71

110.17

108.80

Reaction channels

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ΔrH(298)

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(B3LYP)/6-311G(d,p)/Lanl2DZ level of theory.

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Solvent Phase

95.43

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Table 2 Zero-point corrected total energy (Hartree) of species involved in hydrolysis reaction in gas and solvent phase calculated at DFT (B3LYP)/6-311G(d,p)/Lanl2DZ level of theory. Gas Phase

Solvent Phase

Reactant

-1349.301487

-1349.322386

TS1

-1425.70846

-1425.736428

IM

-964.8688866

-964.8898674

TS2

-1041.275287

-1041.310151

Product

-580.4319577

-580.4515918

H2O

-76.42682663

HCl

-460.8270136

us

cr

ip t

Species

-76.43411848

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pt

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-460.8305407

13

Page 13 of 19

Legend to Figures 1. Scheme 1 Reaction steps in trans-[PtCl2(dimethylamine)(isopropylamine)] hydrolysis 2. Fig. 1. Structural formula of trans-[PtCl2(dimethylamine)(isopropylamine)] 3. Fig. 2. Optimized geometries of the reactant, transition state and product during

ip t

hydrolysis 4. Fig. 3. Potential energy surface (PES) of the first and second hydrolysis steps of gas

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phase (black) and in aqueous phase (red).

14

Page 14 of 19

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*Graphical Abstract (pictogram) (for review)

Page 15 of 19

Page 16 of 19

ed

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i

Page 17 of 19

ed

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Page 18 of 19

d

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Page 19 of 19

ed

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