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

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
• adenin chemie   MeSH
• cisplatina chemie   MeSH
• cytosin chemie   MeSH
• guanin chemie   MeSH
• heteroduplexy nukleové kyseliny chemie   MeSH
• jednovláknová DNA chemie   MeSH
• molekulární modely MeSH
• platina chemie   MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• adenin MeSH
• cisplatina MeSH
• cytosin MeSH
• guanin MeSH
• heteroduplexy nukleové kyseliny MeSH
• jednovláknová DNA MeSH
• platina MeSH

Pentaaqua complexes of Cu(I) with guanine were optimized at the DFT B3PW91/6-31G(d) level. For the most stable structures, vibration frequencies and NBO charges were computed followed by energy analyses. The order of individual conformers was very sensitive to the method and basis sets used for the calculation. Several conformers are practically degenerated in energy. The inclusion of an entropy term changes the order of the conformers' stability. Water molecules associated at the N9 position of guanine are favored by the inclusion of the entropy correction. Bonding energies of Cu-O(aqua) interactions were estimated to be about 60 kcal mol(-1) and for Cu-N7 bonding in the range of 75-83 kcal mol(-1). The broad range in Cu-N interaction energies demonstrates the role of induction effects caused by water molecules associated at the various sites of guanine. The charge distribution of the guanine molecule is changed remarkably by the coordination of a Cu(I) cation, which can also change the base-pairing pattern of the guanine.

• MeSH
• chemické modely * MeSH
• elektrony * MeSH
• guanin chemie   MeSH
• měď chemie   MeSH
• molekulární struktura MeSH
• termodynamika MeSH
• voda chemie   MeSH
• vodíková vazba MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH
• Research Support, U.S. Gov't, Non-P.H.S. MeSH
• Názvy látek
• guanin MeSH
• měď MeSH
• voda MeSH