title: Comparative study of hydrolytic and electron-driven processes in carboplatin biotransformation.
abstract: The results of computational simulation of reaction courses mimicking the transformation of carboplatin from pro-drug into its active shape, responsible for cytotoxic effect, are reported. Implementing the density functional theory (DFT) calculations and the supermolecular approach, we explored the pathways representing two disparate models of carboplatin bioactivation: (1) based on paradigm of carboplatin aquation, and (2) based on new hypothesis that transformation is controlled by electron-transfer processes. The calculated geometrical and thermodynamic parameters were used for evaluation of pathways. In contrast to carboplatin hydrolysis, representing a typical two stage SN2 mechanism, the postulated electron-driven reactions proceed under the dissociative electron attachment (DEA) mechanism. The reaction profiles predict endothermic effect in both stages of hydrolytic course and final exothermic effects for electron-driven processes. The most effective are hybrid processes including two-stages: water and subsequent electron impact on transformed carboplatin. The aqua-products, manifesting strong electron-affinity, can be the active form of drug capable to cytotoxic interaction with DNA, not only as alkylating agent but also as electron-acceptor. Concluding, the hybrid transformation of carboplatin is more favourable than hydrolytic.
authors.affiliation: Faculty of Chemistry, Wrocław University, F. Joliot-Curie 14, 50-370 Wrocław, Poland. Electronic address: janina.kuduk-jaworska@chem.uni.wroc.pl.
authors.forename: Janina
authors.initials: J
authors.lastname: Kuduk-Jaworska
authors.affiliation: Faculty of Chemistry, Wrocław University, F. Joliot-Curie 14, 50-370 Wrocław, Poland. Electronic address: jerzy.janski@chem.uni.wroc.pl.
authors.forename: Jerzy J
authors.initials: JJ
authors.lastname: Jański
authors.affiliation: Advanced Materials Engineering and Modelling Group, Faculty of Chemistry, Wrocław University of Science and Technology, Wyb. Wyspiańskiego 27, 50-370 Wrocław, Poland. Electronic address: szczepan.roszak@pwr.edu.pl.
authors.forename: Szczepan
authors.initials: S
authors.lastname: Roszak
mesh_terms: D001711:Biotransformation; D016190:Carboplatin / Q000737:chemistry / Q000493:pharmacokinetics; D008954:Models, Biological; D008956:Models, Chemical
chemical_list: D016190:Carboplatin
keywords: Carboplatin transformation; DFT calculations; Electron-driven reactions; Hybrid mechanism; Nonclassical Pt-water interactions