TY - JOUR
T1 - New Insights into the Reactivity of Cisplatin with Free and Restrained Nucleophiles: Microsolvation Effects and Base Selectivity in Cisplatin–DNA Interactions
AU - de Cózar, Abel
AU - Larrañaga, Olatz
AU - Bickelhaupt, F. Matthias
AU - San Sebastián, Eider
AU - Ortega-Carrasco, Elisabeth
AU - Maréchal, Jean Didier
AU - Lledós, Agustí
AU - Cossío, Fernando P.
PY - 2016/12/5
Y1 - 2016/12/5
N2 - © 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.
AB - © 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.
KW - activation-strain model
KW - cisplatin
KW - density functional calculations
KW - kinetics
KW - nucleophiles
U2 - 10.1002/cphc.201600982
DO - 10.1002/cphc.201600982
M3 - Article
VL - 17
SP - 3932
EP - 3947
IS - 23
ER -