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.

• Klíčová slova
• Anticancer drug, Computational chemistry, Density functional theory, Heavy metal, Thermodynamics,
• MeSH
• chelátory chemie   MeSH
• cisplatina chemie   MeSH
• dipeptidy chemie   MeSH
• histidin chemie   MeSH
• kinetika MeSH
• methionin chemie   MeSH
• protinádorové látky chemie   MeSH
• teorie funkcionálu hustoty * MeSH
• termodynamika MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• chelátory MeSH
• cisplatina MeSH
• dipeptidy MeSH
• histidin MeSH
• methionin MeSH
• protinádorové látky 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
• chemické modely MeSH
• kinetika MeSH
• kvantová teorie MeSH
• ligandy MeSH
• molekulární modely MeSH
• organoplatinové sloučeniny chemie   MeSH
• oxidace-redukce MeSH
• protinádorové látky chemie   MeSH
• termodynamika MeSH
• voda chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• amminedichloro(cyclohexylamine)platinum(II) MeSH Prohlížeč
• JM 335 MeSH Prohlížeč
• ligandy MeSH
• organoplatinové sloučeniny MeSH
• protinádorové látky MeSH
• satraplatin MeSH Prohlížeč
• voda 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
• chemické modely * MeSH
• cisplatina chemie   farmakologie   MeSH
• elektrony MeSH
• inhibiční koncentrace 50 MeSH
• kinetika MeSH
• lidé MeSH
• ligandy MeSH
• nádorové buněčné linie MeSH
• organoplatinové sloučeniny chemie   farmakologie   MeSH
• počítačová simulace * MeSH
• protinádorové látky chemie   farmakologie   MeSH
• sloučeniny platiny chemie   MeSH
• termodynamika MeSH
• thiazoly chemie   farmakologie   MeSH
• voda chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• srovnávací studie MeSH
• Názvy látek
• amminedichloro(cyclohexylamine)platinum(II) MeSH Prohlížeč
• cisplatina MeSH
• ligandy MeSH
• organoplatinové sloučeniny MeSH
• platinum chloride MeSH Prohlížeč
• protinádorové látky MeSH
• sloučeniny platiny MeSH
• thiazoly MeSH
• trans-(PtCl2(NH3)(thiazole)) MeSH Prohlížeč
• voda MeSH