The kinetics of the hydration reaction on trans-[Pt(NH3)2(pyrX)Cl]+ (pyr = pyridine) complexes (X = OH-, Cl-, F-, Br-, NO2 -, NH2, SH-, CH3, C≡CH, and DMA) was studied by density functional theory calculations in the gas phase and in water solution described by the implicit polarizable continuum model method. All possible positions ortho, meta, and para of the substituent X in the pyridine ring were considered. The substitution of the pyr ligand by electron-donating X's led to the strengthening of the Pt-N1(pyrX) (Pt-NpyrX) bond and the weakening of the trans Pt-Cl or Pt-Ow bonds. The electron-withdrawing X's have exactly the opposite effect. The strengths of these bonds can be predicted from the basicity of sigma electrons on the NpyrX atom determined on the isolated pyrX ligand. As the pyrX ring was oriented perpendicularly with respect to the plane of the complex, the nature of the X···Cl electrostatic interaction was the decisive factor for the transition-state (TS) stabilization which resulted in the highest selectivity of ortho-substituted systems with respect to the reaction rate. Because of a smaller size of X's, the steric effects influenced less importantly the values of activation Gibbs energies ΔG ⧧ but caused geometry changes such as the elongation of the Pt-NpyrX bonds. Substitution in the meta position led to the highest ΔG ⧧ values for most of the X's. The changes of ΔG ⧧ because of electronic effects were the same in the gas phase and the water solvent. However, as the water solvent dampened electrostatic interactions, 2200 and 150 times differences in the reaction rate were observed between the most and the least reactive mono-substituted complexes in the gas phase and the water solvent, respectively. An additional NO2 substitution of the pyrNO2 ligand further decelerated the rate of the hydration reaction, but on the other hand, the poly-NH2 complexes were no more reactive than the fastest o-NH2 system. In the gas phase, the poly-X complexes showed the additivity of the substituent effects with respect to the Pt-ligand bond strengths and the ligand charges.

• Publication type
• Journal Article MeSH

Interaction of cisplatin in activated diaqua-form with His-Met dipeptide is explored using DFT approach with PCM model. First the conformation space of the dipeptide is explored to find the most stable structure (labeled 0683). Several functionals with double-zeta basis set are used for optimization and obtained order of conformers is confirmed by the CCSD(T) single-point calculations. Supermolecular model is used to determine reaction coordinate for the replacement of aqua ligands consequently by N-site of histidine and S-site of methionine and reversely. Despite the monoadduct of Pt-S(Met) is thermodynamically less stable this reaction passes substantially faster (by several orders of magnitude) than coordination of cisplatin to histidine. The consequent chelate formation occurs relatively fast with energy release up to 12 kcal mol-1.

• Keywords
• Anticancer drug, Computational chemistry, Density functional theory, Heavy metal, Thermodynamics,
• MeSH
• Chelating Agents chemistry   MeSH
• Cisplatin chemistry   MeSH
• Dipeptides chemistry   MeSH
• Histidine chemistry   MeSH
• Kinetics MeSH
• Methionine chemistry   MeSH
• Antineoplastic Agents chemistry   MeSH
• Density Functional Theory * MeSH
• Thermodynamics MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Chelating Agents MeSH
• Cisplatin MeSH
• Dipeptides MeSH
• Histidine MeSH
• Methionine MeSH
• Antineoplastic Agents MeSH

In the study behavior of molecular electrostatic potential, averaged local ionization energy, and reaction electronic flux along the reaction coordinate of hydration process of three representative Ru(II) and Pt(II) complexes were explored using both post-HF and DFT quantum chemical approximations. Previously determined reaction mechanisms were explored by more detailed insight into changes of electronic properties using ωB97XD functional and MP2 method with 6-311++G(2df,2pd) basis set and CCSD/6-31(+)G(d,p) approach. The dependences of all examined properties on reaction coordinate give more detailed understanding of the hydration process.

• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Hydration reactions of two anticancer Pt(IV) complexes JM149 and JM216 (Satraplatin) were studied computationally together with the hydration of the Pt(II) complex JM118, which is a product of the Satraplatin reduction. Thermodynamic and kinetic parameters of the reactions were determined at the B3LYP/6-311++G(2df.2pd)//B3LYP/6-31 + G(d)) level of theory. The water solution was modeled using the COSMO implicit solvation model, with cavities constructed using Klamt's atomic radii. It was found that hydration of the Pt(IV) complexes is an endergonic/endothermic reaction. It follows the (pseudo)associative mechanism is substantially slower (k ≈ 10(-11) s(-1)) than the corresponding reaction of Pt(II) analogues ((k ≈ 10(-5) s(-1)). Such a low value of the reaction constant signifies that the hydration of JM149 and Satraplatin is with high probability a kinetically forbidden reaction. Similarly to JM149 and Satraplatin, the hydration of JM118 is an endothermic/endoergic reaction. On the other hand, the kinetic parameters are similar to those of cisplatin Zimmermann et al. (J Mol Model 17:2385-2393, 2011), allowing the hydration reaction to occur at physiological conditions. These results suggest that in order to become active Satraplatin has to be first reduced to JM118, which may be subsequently hydrated to yield the active species.

• MeSH
• Models, Chemical MeSH
• Kinetics MeSH
• Quantum Theory MeSH
• Ligands MeSH
• Models, Molecular MeSH
• Organoplatinum Compounds chemistry   MeSH
• Oxidation-Reduction MeSH
• Antineoplastic Agents chemistry   MeSH
• Thermodynamics MeSH
• Water chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• amminedichloro(cyclohexylamine)platinum(II) MeSH Browser
• JM 335 MeSH Browser
• Ligands MeSH
• Organoplatinum Compounds MeSH
• Antineoplastic Agents MeSH
• satraplatin MeSH Browser
• Water MeSH

The thermodynamics of cisplatin and transplatin hydration is studied within the model of constant pH solution. Several implicit solvation models were chosen for the determination of pK(a) and pK constants of the hydration reactions. The polarizable dielectric model (DPCM), integral equation formalism polarizable model (IEFPCM), and polarizable conductor model (CPCM) were combined with the 'united atom model for Hartree-Fock' (UAHF) method for cavity construction and the B3LYP/6-31++G(2dp,2pd) level of calculations for the determination of electronic energies. The results were compared with the COSMO-RS and SM8 model developed by Truhlar (with M06 and MPWX functionals and the charge model CM4). The RMS difference between experimental and calculated pK(a) values of cis/transplatin, water, HCl, and NH (4) (+) was used to evaluate accuracy of calculations. The DPCM model was confirmed to perform the best. The predicted pK(a) constants were used in Legendre transformation for the estimation of the ΔG' energies in the constant-pH model. The dependence of the pK constant on pH is plotted and compared with experimental value at pH=7.4. The influence of various chloride concentrations on the molar fractions of dissolved forms of cisplatin is examined for the DPCM model. The increased ratio of cisplatin active aqua-forms is clearly visible for 4 mM chloride solution in comparison with 104 mM Cl(-) concentration.

• MeSH
• Algorithms MeSH
• Models, Chemical MeSH
• Chlorides chemistry   MeSH
• Cisplatin chemistry   MeSH
• Hydrolysis MeSH
• Coordination Complexes chemistry   MeSH
• Hydrogen-Ion Concentration MeSH
• Quantum Theory MeSH
• Computer Simulation MeSH
• Thermodynamics * MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Chlorides MeSH
• Cisplatin MeSH
• Coordination Complexes MeSH
• transplatin MeSH Browser

Treatment strategies for tumour diseases are progressively focusing on personalization of medicine. However, this focus requires methods revealing the early general biological mechanisms, including the formation anti-cancer drugs' resistance. The low molecular mass protein metallothionein is thought to be the crucial for the formation of resistance in tumour treatment based on the platinum-cytostatics. The interactions between metallothionein (MT) and cisplatin were determined by the adsorptive transfer stripping technique coupled with the differential pulse votlammetry Brdickás reaction. The signals related to the MT-cisplatin complex appeared at -0.9 V. The formation of this complex depended on the time of interaction between cisplatin and MT. The complex formation was consequently confirmed by quartz crystal microbalance analyses. The formation of this complex was detectable even after a 20 s long interaction. Moreover, we detected presence of MT-cisplatin complex in the blood of male rats treated with this drug.

• Keywords
• Brdickás reaction, Cancer, Cisplatin, Metallothionein, Protein-Drug Interaction, Quartz Crystal Microbalance, Voltammetry,
• Publication type
• Journal Article MeSH

Three potential anticancer agents {trans-[PtCl(2)(NH(3))(thiazole)], cis-[PtCl(2)(NH(3))(piperidine)], and PtCl(2)(NH(3))(cyclohexylamine) (JM118)} were explored and compared with cisplatin and the inactive [PtCl(dien)](+) complex. Basic electronic properties, bonding and stabilization energies were determined, and thermodynamic and kinetic parameters for the aquation reaction were estimated at the B3LYP/6-311++G(2df,2pd) level of theory. Since the aquation process represents activation of these agents, the obtained rate constants were compared with the experimental IC(50) values for several tumor cells. Despite the fact that the processes in which these drugs are involved and the way in which they affect cells are very complex, some correlations can be deduced.

• MeSH
• Models, Chemical * MeSH
• Cisplatin chemistry   pharmacology   MeSH
• Electrons MeSH
• Inhibitory Concentration 50 MeSH
• Kinetics MeSH
• Humans MeSH
• Ligands MeSH
• Cell Line, Tumor MeSH
• Organoplatinum Compounds chemistry   pharmacology   MeSH
• Computer Simulation * MeSH
• Antineoplastic Agents chemistry   pharmacology   MeSH
• Platinum Compounds chemistry   MeSH
• Thermodynamics MeSH
• Thiazoles chemistry   pharmacology   MeSH
• Water chemistry   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• amminedichloro(cyclohexylamine)platinum(II) MeSH Browser
• Cisplatin MeSH
• Ligands MeSH
• Organoplatinum Compounds MeSH
• platinum chloride MeSH Browser
• Antineoplastic Agents MeSH
• Platinum Compounds MeSH
• Thiazoles MeSH
• trans-(PtCl2(NH3)(thiazole)) MeSH Browser
• Water MeSH

In this study, various platinum cross-links in DNA bases were explored. Some of these structures occur in many cis/trans-platinated double-helixes or single-stranded adducts. However, in the models studied, no steric hindrance from sugar-phosphate backbone or other surroundings is considered. Such restrictions can change the bonding picture partially but hopefully the basic energy characteristics will not be changed substantially. The optimization of the structures explored was performed at the DFT level with the B3LYP functional and the 6-31G(d) basis set. Perturbation theory at the MP2/6-31++G(2df,2pd) level was used for the single-point energy and 6-31+G(d) basis set for the electron-property analyses. It was found that the most stable structures are the diguanine complexes followed by guanine-cytosine Pt-cross-links, ca 5 kcal mol(-1) less stable. The adenine-containing complexes are about 15 kcal mol(-1) below the stability of diguanine structures. This stability order was also confirmed by the BE of Pt-N bonds. For a detailed view on dative and electrostatic contributions to Pt-N bonds, Natural Population Analysis, determination of electrostatic potentials, and canonical Molecular Orbitals description of the examined systems were used.

• MeSH
• Adenine chemistry   MeSH
• Cisplatin chemistry   MeSH
• Cytosine chemistry   MeSH
• Guanine chemistry   MeSH
• Nucleic Acid Heteroduplexes chemistry   MeSH
• DNA, Single-Stranded chemistry   MeSH
• Models, Molecular MeSH
• Platinum chemistry   MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Adenine MeSH
• Cisplatin MeSH
• Cytosine MeSH
• Guanine MeSH
• Nucleic Acid Heteroduplexes MeSH
• DNA, Single-Stranded MeSH
• Platinum MeSH