Quantum chemical studies on binding of ccis-[PtCl2(iPram)(Hpz)] to guanosine - Pham Vu Nhat

Vietnam Journal of Science and Technology 55 (6A) (2017) 51-62 QUANTUM CHEMICAL STUDIES ON BINDING OF cis-[PtCl2(iPram)(Hpz)] TO GUANOSINE Pham Vu Nhat Department of Chemistry, Can Tho University, 3/2 Street, Can Tho City, Viet Nam Email: nhat@ctu.edu.vn Received: 17 June 2017; Accepted for publication: 21 December 2017 ABSTRACT Quantum chemical calculations are employed to examine the interactions of hydrolysis products of cis-[PtCl2(iPram)(Hpz)] with the purine base site of DNA using guanosine as a model reactant. Thermodynamic parameters, electronic structures, bonding characteristics and spectroscopic properties of the resulting complexes are investigated in the framework of density functional theory (B3LYP functional) along with correlation consistent basis sets. Computed results show that these interactions are dominated by electrostatic effects, namely H-bond contributions. Another remarkable finding is that the replacement of amine groups by larger ones accompanies with a moderate reaction between Pt II and guanosine. Keywords: cisplatin, Density Functional Theory, guanine, anticancer, hydrogen bonding 1. INTRODUCTION Cisplatin or cis-diamminedichloroplatinum(II) (cis-[Pt(Cl)2(NH3)2] or cis-DDP), is a widely-used antitumor drug which has been particularly successful in treatment of various fatal diseases, including testicular, ovarian, head and neck cancers [1, 2]. Unfortunately, the drug presents many limitations, for example, several side effects (such as nausea, ear damage, and vomiting) or both intrinsic and acquired resistance [3, 4, 5]. Therefore, for the past decades much effort has been devoted to the exploitation of alternative platinum complexes in order to limit these drawbacks [6]. However, the search for analogous compounds that outperform cisplatin has proved to be an extremely difficult task, not only because of the diversity of the compositions, structures and properties of replaced ligands, but also due to the lack of quantitative atomic level information about the features controlling Pt-DNA interactions. Indeed, thousands of platinum compounds have been synthesized so far [2, 7], but only a few new agents such as oxaliplatin, carboplatin and nedaplatin have been registered worldwide and entered clinical practice [8]. In this context, a thorough understanding of interactions between the Pt and DNA building blocks is thought to be helpful in designing cisplatin analogues. Pham Vu Nhat 52 Recently, quantum chemical calculations have widely been used and made significant contributions to a deeper understanding of the interaction mechanisms between cisplatin and DNA. From the early time, using Hartree-Fock (HF) model in conjunction with the minimal basis set STO-3G, Kozelka and co-workers were able to reproduce some structural patterns of cis-DDP–base DNA [9, 10]. Other remarkable results on structural aspects of the complexes between platinum and biomolecules come from the Carloni group, based on the application of the density functional theory (DFT) [11, 12]. The hydrolysis of cisplatin and some features of the changes in electronic structure including the influence of platination on base pairs, or the proton affinity have also been intensively studied at different levels of theory [13, 14, 15, 16, 17]. Recently, a combined IRMPD, MS/MS and theoretical study on interactions of cisplatin and base purines has been intensively examined with the aim to provide an accurate characterization of the resulting complexes [18]. In this work, we carry out an examination on the interactions between an asymmetric derivative of cisplatin, i.e. cis-[PtCl2(iPram)(Hpz)] (where iPram is isopropylamine and Hpz is pyrazole), and DNA base sites using guanosine as a model reactant. The cytotoxicity of the complex in several human cell lines was found to be lower than that of cisplatin [19], but further information is still not clarified. Although geometric parameters or spectroscopic information can be sufficiently collected by experimental techniques, it is more difficult to combine structural data with energetic properties using only traditional observations. Advanced quantum chemical methods become potential and effective tools to achieve these purposes. 2. MATERIALS AND METHODS All calculations are performed using the Gaussian 09 suite of program [20] in the framework of density functional theory [21]. The hybrid B3LYP functional in conjunction with the correlation consistent cc-pVTZ-PP and cc-pVTZ basis sets is employed for geometry optimization and energetic calculations as well. The basis set with an effective core potential (ECP) cc-pVTZ-PP [22] is applied for platinum, while the all electrons cc-pVTZ basis set is used for the non-metals. The ECP cc-pVTZ-PP basis set already includes relativistic effects that are very crucial in treatment of heavy elements such as platinum. Harmonic vibrational frequencies are also calculated to confirm the character of optimized geometries as local minima or transition states on the potential energy surface, and to estimate the zero-point vibrational energy (ZPE) corrections. The natural bond orbital (NBO) charges of atoms are computed using the NBO5.G code [23]. We exploit NBO charges for electron population analysis instead of Mulliken charges because the former are expected to be more reliable [24]. Previous studies confirm that after entering the cell by passive diffusion through the cell membrane cisplatin undergoes spontaneous hydrolysis via nucleophilic substitution of chloride with water to form cationic complexes [Pt(NH3)2(H2O)Cl] + and [Pt(NH3)2(H2O)2] 2+ [25]. This process is a fundamental step determining the anticancer activity of cisplatin as it leads to reactive metabolites that ultimately give rise to DNA adducts [26]. Both complexes can be substituted easily by donor ligands such as nitrogen-containing bases of DNA with the loss of water, but it is currently unclear whether the monoaqua or diaqua species to be more important [27]. Previous studies have shown that interactions of Pt II with guanine prefer to occur at the N7 position. Hence, current work just pays attention to the examine the binding of cis- Quantum chemical studies on binding of cis-[PtCl2(iPram)(Hpz)] to guanosine 53 [PtCl2(iPram)(Hpz)] to guanosine via the N-7 site. The exchange-ligand energies (E T ) of these complexes with guanine are computed based on following process: [PtLL’(H2O)Cl] + + G → [PtLL’(G)Cl]+ + H2O As for a convention, a negative value of E T corresponds to a favorable interchange, but the selectivity is low. In addition, this parameter can be used to evaluate the relative stability of a specific Pt-guanosine complex. 3. RESULTS AND DICUSSION 3.1. Interactions of [Pt(iPram)(Hpz)(H2O)Cl] + with guanosine Similar to [PtCl2(NH3)2], the [PtCl2(iPram)(Hpz)] has two structural isomers as shown in Figure 1. At the level of theory applied in this study, the cis form is predicted to be somewhat less stable than the trans counterpart, being separated by about 6.5 kcal/mol. In the [PtCl2(iPram)(Hpz)], the distance of Pt – Cl bonds, being about 2.31 Å computed at B3LYP/cc-pVTZ(PP) leval, is quite longer than that of Pt – N bonds. Indeed, the bond lengths of Pt – NH (Hpz) and Pt – NH2 (iPram) are predicted to be 1.99 and 2.12 Å, respectively. Therefore, in ligand-exchange reactions, the anions Cl – are seemingly more willing to be removed than the amine groups. Figure 1. Two structural isomers of [PtCl2(iPram)(Hpz)]. The possible isomers detected for cation [Pt(iPram)(Hpz)(Go)Cl] + , along with their relative energies computed at the B3LYP/cc-pVTZ-(PP) + ZPE level, are displayed in Figure 2. The result shows that the resulting complexes are stabilized as they can form a hydrogen bond via the CO group with either NH2 (iPram) or NH (Hpz) group. Pham Vu Nhat 54 Pt(iPram)Hpz(Go)-1; [0.0] Pt(iPram)Hpz(Go)-2; [0.8] Pt(iPram)Hpz(Go)-3; [6.7] Pt(iPram)Hpz(Go)-4; [7.8] Figure 2. Possible structures obtained for [Pt(iPram)(Hpz)(Go)Cl] + complex. The values (kcal/mol) in square brackets are their relative energies. As shown in Figure 2, two lowest-energy structures obtained for the cation [Pt(iPram)(Hpz)(Go)Cl] + are Pt(iPram)Hpz(Go)-1 and Pt(iPram)Hpz(Go)-2. These forms are stabilized owing to electrostatic interactions either between the NH group on pyrazole (Hpz) or the NH2 group on isopropylamine (iPram) and O atom of guanosine. On the contrary, both forms Pt(iPram)Hpz(Go)-3 and Pt(iPram)Hpz(Go)-4 become significantly less stable due to lack of a H bond as in Pt(iPram)Hpz(G)-1 though both structures are quite similar. These forms are evaluated to be around 6.7 – 7.8 kcal/mol higher in energy than the ground state. Thus such a gap can be considered as the H-bond energy in the complex [Pt(iPram)(Hpz)(Go)Cl] + . Quantum chemical studies on binding of cis-[PtCl2(iPram)(Hpz)] to guanosine 55 Table 1. Exchange-ligand energy (E T ) and bond lengths Pt–N7; NH O in [Pt(iPram)(Hpz)(G)Cl]+. Structure E T (kcal/mol) ( ) ( ) Pt(iPram)Hpz(Go)-1 –43.1 2.05 1.72 Pt(iPram)Hpz(Go)-2 –42.3 2.04 1.82 Pt(iPram)Hpz(Go)-3 –36.4 2.06 – Pt(iPram)Hpz(Go)-4 –35.3 2.06 – Table 1 summarizes computed results obtained for species [Pt(iPram)(Hpz)(Go)Cl] + . The ligand exchange energy at the B3LYP/cc-pVTZ/cc-pVTZ-PP level for the monoaqua complex ranges from –43.1 kcal/mol (Pt(iPram)Hpz(G)-1) to –35.3 kcal/mol (Pt(iPram)Hpz(Go)-4). The values can be considered as enthalpy changes of reactions. It follows from the Table 1 that if the entropy factor is negligible these reactions would occur spontaneously and be exothermic. In addition, the absolute values of the reaction energy (above 35 kcal/mol) are high enough for unambiguous conclusions. At the same level employed in this study, the ligand exchange energy of cis- [Pt(NH3)2(H2O)Cl] + with guanosine is computed to be around –46.3 kcal/mol. This value is thus more negative than that of the derivative [Pt(iPram)(Hpz)(H2O)Cl] + . Hence it can be expected that the former is more willing to exchange the water group by means of a base than the latter. In other word, the replacement of ammine groups by larger ones such as iPram and Hpz accompanies with a somewhat moderate reaction between Pt II and guanosine. 3.2. Interactions of [Pt(iPram)(Hpz)(H2O)2] 2+ with guanosine The replacement of two aqua ligands in the cation [Pt(iPram)(Hpz)(H2O)2] 2+ by guanosine molecules gives rise to the complex [Pt(iPram)(Hpz)(Go)2] 2+ with possible structures plotted in Figure 3. It can be seen that all the structures are stabilized due to hydrogen bonds, even with the least stable form. In both forms Pt(iPram)Hpz(Go)2-1 and -2, hydrogen bonds are established between the hydrogen atom of the Hpz and iPram ligands and the oxygen atom at the C6 position. Their relative energy at the applied level of theory in this work is insignificant, being only around 0.7 kcal/mol. Within the error bar of the computational methods, these forms can be regarded to be degenerate and each of them can emerge as the ground state. Table 2. Exchane-ligand energy (E T ) and some geometric parameters in [Pt(iPram)(Hpz)(Go)2] 2+ . Structure E T (kcal/mol) ( ) ( ) Pt(iPram)Hpz(Go)2-1 –118 2.06 1.77; 1.88 Pt(iPram)Hpz(Go)2-2 –117 2.07 1.77; 1.89 Pt(iPram)Hpz(Go)2-3 –114 2.06 1.77 Pt(iPram)Hpz(Go)2-4 –112 2.05 1.90 On the contrary, the Pt(iPram)Hpz(Go)2-3 becomes less stable as only one H-bond via the Hpz group is allowed. This conformation is computed to be about 3.5 eV above the most stable Pt(iPram)Hpz(Go)2-1, which contains two H-bonds. Similarly, Pt(iPram)Hpz(Go)2-4 is least stable because it can form one H-bond via the iPram ligand. As expected, the NH group of Pham Vu Nhat 56 pyrazole is a much better hydrogen-bond donor than the NH2 group of iPram. Indeed, the stronger interaction is reflected in the distance of the bond in platinated guanosine adducts as shown in Table 2. The hydrogen bond is computed to be around 1.77 as compared to the value of 1.89 – 1.89 for . The hydrogen bond is thus expected to contribute approximately 6.0 kcal/mol to the bond energy in the complex [Pt(iPram)(Hpz)(Go)2] 2+ . Pt(iPram)HpzAq(Go)-1; [0.0] Pt(iPram)HpzAq(Go)-2; [0.7] Pt(iPram)HpzAq(Go)-3; [3.5] Pt(iPram)HpzAq(Go)-1; [6.0] Figure 3. Possible structures detected for [Pt(iPram)(Hpz)(G)(H2O)] 2+ . The values (kcal/mol) in square brackets are their relative energies. The ligand exchange energies (E T ) along with the bond lengths Pt–N7(G) and distances of H-bonds XH O are summarized in Table 2. The results indicate that if the diaqua complex is used, the platination of guanine is more thermodynamically preferable by around 23 kcal/mol. Quantum chemical studies on binding of cis-[PtCl2(iPram)(Hpz)] to guanosine 57 The E T values predicted for the diaqua complex vary from –118 to –112 kcal/mol (Table 2), as compared to the values of –43 to –35 kcal/mol calculated for the monoaqua species (Table 1). Thus, in terms of thermodynamics, cation [Pt(iPram)(Hpz)(H2O)2] 2+ is more willing to interchange one water ligand with guanosine than the monoaqua complex [Pt(iPram)(Hpz)(H2O)Cl] + . 3.3. Changes in geometric parameters and vibrational frequencies As illustrated in Table 3, the introduction of NH ⋯ O interaction leads to significant changes in bond lengths and vibrational frequencies of the bonding N–H in systems considered. Our calculations show that as a consequence of a strong electrostatic interaction, bond lengths of N–H and HN–H are increased by 0.02 – 0.03 Å. Such observations are clearly manifested in the frequency red-shift of the stretching modes υ(N – H) and υ(HN – H), being around 320 – 477 cm –1 (Table 3). For instance, the N–H and NH–H distances of Hpz and iPram ligands in [Pt(iPram)(Hpz)(H2O)Cl] + is computed to be 1,00 and 1,02 Å, respectively, as compared to a value of 1,03 Å in Pt(iPram)Hpz(Go)-1 and Pt(iPram)Hpz(Go)-2. For example, in agreement the change in bond lengths, the stretching mode υ(N – H) is significantly red-shifted to 3173 cm–1 when forming the complex Pt(iPram)Hpz(Go)-1, while these vibrations are predicted to occur at 3650 cm –1 in [Pt(iPram)(Hpz)(H2O)Cl] + . Forming the hydrogen bond influences not only on X–H bonds but also on the carbonyl group of guanine. This phenomenon can be explained by the formation of a hydrogen bond weakening the double bond character, and also by the proximity of the platinum ion. At the applied level of theory, the stretching mode C=O is computed to be about 1796 cm -1 in free guanosine. For Pt(iPram)Hpz(G)-1, due to the presence of the hydrogen bond, a significant red- shift is observed as the mode υ(C=O) now shifts to 1728 cm–1. Although, the experimental IR spectra for complexes considered in this study have not been published so far, they are reported here as predictions that may allow one to verify the optimal structures when the spectroscopic information is available. Figures 5 and 6 are plots of the vibrational signatures for lowest-lying states of the monoaqua and diaqua along with [Pt(iPram)(Hpz)(Go)Cl] + and [Pt(iPram)(Hpz)(Go)2] + adducts. Table 3. The changes in bond lengths ( , ), harmonic frequencies ( , cm –1 ) of X–H bonds when forming H-bonds. Complex Bonding Complex Bonding Pt(iPram)Hpz(Go)-1 N–H 0.03 –477 Pt(iPram)HpzAq(Go)-1 HN–H 0.00 –11.0 Pt(iPram)Hpz(Go)-2 N–H 0.00 –4.00 Pt(iPram)HpzAq(Go)-2 HN–H 0.02 –207 Pt(iPram)Hpz(Go)-3 N–H 0.02 –350 Pt(iPram)HpzAq(Go)-3 HN–H 0.00 –15.0 Pt(iPram)Hpz(Go)-4 N–H 0.00 5.00 Pt(iPram)HpzAq(Go)-4 HN–H 0.02 –220 Pham Vu Nhat 58 Figure 4. Vibrational signatures of [Pt(iPram)(Hpz)(H2O)Cl] + (above) and [Pt(iPram)(Hpz)(Go)Cl] + (below) in their lowest-lying states. Figures 4 and 5 show that the IR spectra of both the monoaqua and diaqua complexes can be classified into two specific regions, namely the finger-print bands 500 – 1700 cm–1 and the X – H stretching bands 3000 – 3700 cm–1. As mentioned above, the vibrational spectra of these systems are strongly dependent on the nature of surrounded atoms. We actually observe significantly large modifications in band intensities and frequencies of the complexes during the interchange water and guanine ligands. The replacement of a water ligand by a guanine not only modifies the vibrational features in the finger-print region, but also leads to large red-shifts of X – H stretching modes in Hpz and water ligands. The spectra of both [Pt(iPram)(Hpz)(H2O)Cl] + and [Pt(iPram)(Hpz)(H2O)2] 2+ show several intense peaks in the range of 3000 – 3700 cm–1. In the computed spectrum of the monoaqua complex the most remarkable are the highest-intensity and highest-frequency features at 3631 and 3793 cm –1 , respectively. These bands correspond to the symmetric and asymmetric O – H stretching modes of the water ligand. The other peak at 3651 cm –1 is associated to the N7–H (Hpz) stretching. For the diaqua complex, two bands at 3800 and 3720 cm –1 are due to the symmetric and antisymmetric stretching of OH (water), while the absorption around 3637 cm –1 is assigned to the N7–H (Hpz) stretching. The stretching modes of NH2 (iPram) also lies in this region, being predicted at ~3490 cm –1 , but they are too weak to observe in the computed spectra. It is clearly seen from Figures 4 and 5 that the appearance of the hydrogen bonding interaction when the H2O molecule is replaced by the guanosine leads to a significant change in the stretching regions. The predicted spectrum of Pt(iPram)Hpz(Go)-1 contains at least four distinct peaks in the range above 3000 cm –1 . The antisymmetric stretching mode of NH2 (guanine) is found to vibrate at 3723 cm –1 . Other main absorptions estimated at 3630, 3575 cm –1 correspond to N9–H and N1–H (guanine) stretches. The highest intensity peak observed at 3238 cm –1 belongs to the stretching of N–H (Hpz). When the hydrogen bond is not allowed, this vibration is calculated to appear around 3651 cm –1 . The highest-energy vibration at 3800 cm –1 is Quantum chemical studies on binding of cis-[PtCl2(iPram)(Hpz)] to guanosine 59 related to the O–H stretching of water ligand that is not involved in hydrogen bonding. For the isomer Pt(iPram)Hpz(Go)2-1, two H-bonds are found between the hydrogen atoms in Hpz, iPram groups and the carbonyl group of guanosine. In addition, the stretching region of Pt(iPram)Hpz(Go)2-1 appears other particularly strong peaks centered at 3500 – 3600 cm –1 , being associated to symmetric stretches of N–H and HNH groups of guanosine. Figure 5. Vibrational signatures of [Pt(iPram)(Hpz)(H2O)2] 2+ (below) and [Pt(iPram)(Hpz)(Go)2] + (above) in their lowest-lying states. 4. CONCLUSIONS In this study, interactions of hydrolysis products of an asymmetric derivative of cisplatin with nucleobase guanosine are systematically are investigated by using quantum chemistry calculations. Density functional method B3LYP combined with correlation consistent basis sets (cc-cc-pVTZ and pVTZ-PP) is employed to examined thermodynamic parameters, electronic structures, bonding characteristics, spectroscopic properties, ... on a variety of chemical systems, rather than using traditional experimental techniques. Computed results show that the resulting complexes are stabilized due to forming strong hydrogen bonds between the H atoms of amine groups and the O6 of guanosine. The structures without H-bond are predicted to be around 1.0 – 8.0 kcal/mol higher in energy. Thus interactions between the derivative cis-[PtCl2(iPram)(Hpz)] with guanosine are dominated by H-bond contributions. Another significant finding is that the replacement of ammine groups by larger ligands such as iPram, Hpz accompanies with a somewhat moderate reaction between Pt II and guanine. The aqua – guanosine ligand exchange energies are computed to be –46 and –43 kcal/mol for cis- [Pt(NH3)2(H2O)Cl] + and [Pt(iPram)(Hpz)(H2O)Cl] + respectively. This is consistent with the experiment that the cytotoxicity of the complex in several human cell lines was found to be Pham Vu Nhat 60 lower than that of cisplatin. The presence of XH O interaction in addition leads to large modifications in bond lengths and vibrational frequencies of the X─H bonds. As a results of strong electrostatic effects, bond lengths of N–H and HN–H are increased by 0.01 – 0.03 Å, corresponding to significant frequency red-shifts of the stretching modes υ(N – H) and υ(HN – H), being around 320 – 477 cm –1 . Even though the experimental IR spectra for systems considered in this study have not been published so far, they are reported here as predictions that may allow one to verify the optimal structures when the spectroscopic information is available. Acknowledgements. The author is grateful to the Interdisciplinary Center for Nanotoxicity, Jackson State University, USA for providing computing resources, and to Can Tho University for financial supports. REFERENCES 1. Gordon M. and Hollander S. – Review of platinum anticancer compounds, J. Med. 24 (1993) 209-65. 2. Weiss R. B. and Christian M. C – New cisplatin analogues in development. A review, Drugs 46 (1993) 360–77. 3. Von Hoff D. D., Schilsky R., Reichert C. M., Reddick R. L., Rozencweig M., Young R. C. and Muggia F. M. – Toxic effects of cis-dichloro-diammineplatinum(II) in man, Cancer Treat. Rep. 63 (1979) 1527–31. 4. Fuertes M. A., Alonso C. and Pérez J. M. – Biochemical modulation of cisplatin mechanisms of action: enhancement of antitumor activity and circumvention of drug resistance, Chem. Rev. 103 (2003) 645–62. 5. Jakupec M. A., Galanski M. and Keppler B. K. – Tumour-inhibiting platinum complexes-- state of the art and future perspectives, Rev. Physiol. Biochem. Pharmacol. 146 (2003) 1– 54. 6. Hegmans A., Berners-Price S. J., Davies M. S., Thomas D. S., Humphreys A. S. and Farrell N. – Long Range 1,4 and 1,6-Interstrand Cross-Links Formed by a Trinuclear Platinum Complex. Minor Groove Preassociation Affects Kinetics and Mechanism of Cross-Link Formation as Well as Adduct Structure, J. Am. Chem. Soc. 126 (2004) 2166– 80. 7. Wong E. and Giandomenico C. M. – Current Status of Platinum-Based Antitumor Drugs, Chem. Rev. 99 (1999) 2451–66. 8. Boulikas T., Pantos A., Bellis E. and Christofis P. – Designing platinum compounds in cancer: structures and mechanisms, Cancer therapy 5 (2007) 537–83. 9. Kozelka J. and Chottard J. C. – How does cisplatin alter DNA structure? A molecular mechanics study on double-stranded oligonucleotides, Biophys. Chem. 35 (1990) 165–78. 10. Kozelka J., Savinelli R., Berthier G., Flament J. P. and Lavery R. J. – Force field for platinum binding to adenine, J. Comput. Chem. 14 (1993) 45–53 11. Carloni P., Andreoni W., Hutter J., Curioni A., Giannozzi P. and Parrinello M. – Structure and bonding in cisplatin and other Pt(II) complexes Chem. Phys. Lett. 234 (1995) 50–56. Quantum chemical studies on binding of cis-[PtCl2(iPram)(Hpz)] to guanosine 61 12. Carloni P., Sprik M. and Andreoni W. – Key Steps of the cis-Platin-DNA Interaction:  Density Functional Theory-Based Molecular Dynamics Simulations, J. Phys. Chem. B 104 (2000) 823–35. 13. Zhang Y., Guo Z. and You X.-Z. – Hydrolysis Theory for Cisplatin and Its Analogues Based on Density Functional Studies, J. Am. Chem. Soc. 123 (2001) 9378–87. 14. Burda J. V., Sponer J. and Leszczynski J. – The influence of square planar platinum complexes on DNA base pairing. An ab initio DFT study, Phys. Chem. Chem. Phys. 3 (2001) 4404–11. 15. Hill G. A., Forde G., Gorb L. and Leszczynski J. – cis‐ Diamminedichloropalladium and its interaction with guanine and guanine–cytosine base pair, Int. J. Quantum Chem. 90 (2002) 1121–28. 16. Monjardet V., Elizondo-Riojas M. A., Chottard J. C., Kozelka J., – A combined effect of molecular electrostatic potential and N7 accessibility explains sequence-dependent binding of cis-[Pt(NH3)2(H2O)2] 2+ to DNA duplexes, J. Angew. Chem., Int. Ed. 41 (2002) 2998–3001. 17. Burda J. V., Zeizinger M., Sponer J. and Leszczynski J. – The Influence of N7 Guanine Modifications on the Strength of Watson−Crick Base Pairing and Guanine N1 Acidity:  Comparison of Gas-Phase and Condensed-Phase Trends, J. Phys. Chem. B 107 (2003) 5349–56. 18. Chiavarino B., Crestoni M. E., Fornarini S., Scuderi D. and Salpin J. Y. – Interaction of Cisplatin with Adenine and Guanine: A Combined IRMPD, MS/MS, and Theoretical Study, J. Am. Chem. Soc. 135 (2013) 1445–55. 19. Pantoja E., Alvarez-Valdes A., Perez J.M., Navarro-Ranninger C. and Reedijk J. – In vitro antitumor activity and interaction with DNA model bases of cis-[PtCl2(iPram)(azole)] complexes and comparison with their trans analogues, Inorganica Chimica Acta 359 (2006) 4335– 42. 20. Frisch M., Trucks G., Schlegel H. B., Scuseria G., Robb M., Cheeseman J., Scalmani G., Barone V., Mennucci B. and Petersson G. E., Gaussian 09: Gaussian, Inc. Wallingford, CT (2009). 21. Pierre H. and Kohn W. – Inhomogeneous Electron Gas, Phys. Rev. B 136 (1964) 864–71. 22. Peterson K. A – Systematically convergent basis sets with relativistic pseudopotentials. II. Small-core pseudopotentials and correlation consistent basis sets for the post-d group 16– 18 elements, J. Chem. Phys. 119 (2003) 11099–113. 23. Glendening E. D. et al., NBO 5.G, Theoretical Chemistry Institute, University of Wisconsin, Madison, WI (2001). 24. Joshi A. M., Tucker M. H., Delgass W. N. and Thomsond K. T. – CO adsorption on pure and binary-alloy gold clusters: A quantum chemical study, J. Chem. Phys. 125 (2006) 194707−11. 25. Davies M. S., Berners-Price S. J. and Hambley T. W. – Slowing of Cisplatin Aquation in the Presence of DNA but Not in the Presence of Phosphate:  Improved Understanding of Sequence Selectivity and the Roles of Monoaquated and Diaquated Species in the Binding of Cisplatin to DNA, Inorg. Chem. 39 (2000) 5603−13. Pham Vu Nhat 62 26. Monjardet-Bas V., Bombard S., Chottard J. C. and Kozelka J. – GA and AG Sequences of DNA React with Cisplatin at Comparable Rates, Chem. Eur. J. 9 (2003) 4739−45. 27. Baik M. H., Friesner R. A. and Lippard S. J. – Theoretical Study of Cisplatin Binding to Purine Bases:  Why Does Cisplatin Prefer Guanine over Adenine?, J. Am. Chem. Soc. 125 (2003) 14082−92.