title: New Insights into the Reactivity of Cisplatin with Free and Restrained Nucleophiles: Microsolvation Effects and Base Selectivity in Cisplatin-DNA Interactions.
abstract: 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.
authors.affiliation: Departamento de Química Orgánica I and ORFEO-CINQA, Kimika Organikoa I Saila, Facultad de Química/Kimika Fakultatea, Universidad del País Vasco, Euskal Herriko Unibertsitatea UPV/EH and Donostia International Physics Center (DIPC), P. K. 1072, 20018, San Sebastián-Donostia, Spain.|IKERBASQUE, Basque Foundation for Science, 48011, Bilbao, Spain.|Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), VU University Amsterdam, De Boelelaan 1083, 1081, HV, Amsterdam, The Netherlands.
authors.forename: Abel
authors.initials: A
authors.lastname: de Cózar
authors.affiliation: Departamento de Química Orgánica I and ORFEO-CINQA, Kimika Organikoa I Saila, Facultad de Química/Kimika Fakultatea, Universidad del País Vasco, Euskal Herriko Unibertsitatea UPV/EH and Donostia International Physics Center (DIPC), P. K. 1072, 20018, San Sebastián-Donostia, Spain.
authors.forename: Olatz
authors.initials: O
authors.lastname: Larrañaga
authors.affiliation: Department of Theoretical Chemistry and Amsterdam Center for Multiscale Modeling (ACMM), VU University Amsterdam, De Boelelaan 1083, 1081, HV, Amsterdam, The Netherlands.|Institute for Molecules and Materials (IMM), Radboud University Nijmegen, Heyendaalseweg 135, NL-6525, AJ, Nijmegen, The Netherlands.
authors.forename: F Matthias
authors.initials: FM
authors.lastname: Bickelhaupt
authors.affiliation: Dept. Química Aplicada, Química Inorgánica, Facultad de Química/ Kimika Fakultatea, Universidad del País Vasco, Euskal Herriko Unibertsitatea UPV/EHU, Paseo Manuel de Lardizabal 3, 20018, San Sebastián-Donostia, Spain.
authors.forename: Eider
authors.initials: E
authors.lastname: San Sebastián
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Ortega-Carrasco
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Maréchal
authors.affiliation: Departament de Química, Universitat Autònoma de Barcelona, 08193, Bellaterra, Barcelona, Spain.
authors.forename: Agustí
authors.initials: A
authors.lastname: Lledós
authors.affiliation: Departamento de Química Orgánica I and ORFEO-CINQA, Kimika Organikoa I Saila, Facultad de Química/Kimika Fakultatea, Universidad del País Vasco, Euskal Herriko Unibertsitatea UPV/EH and Donostia International Physics Center (DIPC), P. K. 1072, 20018, San Sebastián-Donostia, Spain.
authors.forename: Fernando P
authors.initials: FP
authors.lastname: Cossío
mesh_terms: D000225:Adenine / Q000737:chemistry*; D002945:Cisplatin / Q000737:chemistry*; D004247:DNA / Q000737:chemistry*; D006147:Guanine / Q000737:chemistry*; D007093:Imidazoles / Q000737:chemistry*; D011789:Quantum Theory; D014867:Water / Q000737:chemistry*
chemical_list: D007093:Imidazoles; D014867:Water; D006147:Guanine; C029899:imidazole; D004247:DNA; D000225:Adenine; D002945:Cisplatin
keywords: activation-strain model; cisplatin; density functional calculations; kinetics; nucleophiles