Wydział Chemii

Janina Kuduk-Jaworska

Jerzy Jański

Szczepan Roszak

2017

Journal of Inorganic Biochemistry

170

148-159

10.1016/j.jinorgbio.2017.02.003

Naukowa

Angielski

Artykuł

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 S_N2 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.

Carboplatin transformation, Electron-driven reactions, density functional calculations, Hybrid mechanism, Nonclassical Pt-water interactions

http://dx.doi.org/10.1016/j.jinorgbio.2017.02.003

http://www.elsevier.com