A mechanism of the intrastrand 1,2-cross-link formation between the double-stranded pGpG·CpC dinucleotide (ds(pGpG)) and fully aquated oxaliplatin cis-[Pt(DACH)(H2O)2](2+) (DACH = cyclohexane-1R,2R-diamine) is presented. All structures of the reaction pathways including the transition states (TSs) were fully optimized in water solvent using DFT methodology with dispersion corrections. Both 5' → 3' and 3' → 5' binding directions were considered. In the first step there is a slight kinetic preference for 5'-guanine (5'G) monoadduct formation with an activation Gibbs free energy of 18.7 kcal/mol since the N7 center of the 5'G base is fully exposed to the solvent. On the other hand, the N7 atom of 3'-guanine (3'G) is sterically shielded by 5'G. The lowest energy path for formation of the 3'G monoadduct with an activation barrier of 19.3 kcal/mol is connected with a disruption of the 'DNA-like' structure of ds(pGpG). Monoadduct formation is the rate-determining process. The second step, chelate formation, is kinetically preferred in the 3' → 5' direction. The whole process of the platination is exergonic by up to -18.8 kcal/mol. Structural changes of ds(pGpG), charge transfer effects, and the influence of platination on the G·C base pair interaction strengths are also discussed in detail.

Department of Laboratory Methods and Information Systems Faculty of Health and Social Studies University of South Bohemia J Boreckého 27 370 11 České Budějovice Czech Republic

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