New Insights into the Reactivity of Cisplatin with Free and Restrained Nucleophiles: Microsolvation Effects and Base Selectivity in Cisplatin–DNA Interactions

Abel de Cózar, Olatz Larrañaga, F. Matthias Bickelhaupt, Eider San Sebastián, Elisabeth Ortega-Carrasco, Jean Didier Maréchal, Agustí Lledós, Fernando P. Cossío

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7 Citations (Scopus)

Abstract

© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim The reactivity of cisplatin towards different nucleophiles has been studied by using density functional theory (DFT). Water was considered first to analyze the factors that govern the transformation of cisplatin into more electrophilic aquated species by using an activation-strain model. It was found that the selectivity and reactivity of cisplatin is a delicate trade-off between strain and interaction energies and that the second chloride is a worse leaving group than the first. When similar studies were carried out with imidazole, guanine (G), and adenine (A), it was found that in general the second nucleophilic substitution reactions have lower activation barriers than the first ones. Finally, simulations of the structural restrictions imposed by the DNA scaffold in intra- and interstrand processes showed that the geometries of the reaction products are nonoptimal with respect to the unrestrained A and G nucleophiles, although the energetic cost is not considerable under physiological conditions, which thus permits nucleophilic substitution reactions that lead to highly distorted DNA.
Original languageEnglish
Pages (from-to)3932-3947
JournalChemPhysChem
Volume17
Issue number23
DOIs
Publication statusPublished - 5 Dec 2016

Keywords

  • activation-strain model
  • cisplatin
  • density functional calculations
  • kinetics
  • nucleophiles

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