title: Neutral and acidic hydrolysis reactions of the third generation anticancer drug oxaliplatin.
abstract: The hydrolysis of oxaliplatin, a third generation anticancer drug, is expected to play an important role in the activation of this compound before it reaches DNA. The first and second hydrolysis corresponding to the addition of the first water molecule concomitant with the ring-opening, followed by addition of a second water and loss of the monodentate oxalato ligand, respectively, were studied combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The reaction was studied in neutral and acidic conditions, and all stationary points have been identified. The computed potential energy surfaces show that, for the neutral hydrolysis, the ring-opening reaction is the rate-limiting process, with an activation barrier of about 28 kcal/mol. For the acid degradation in water, according to experimental data, the reaction is expected to proceed in a faster biphasic process, and the rate-limiting process is the ligand detachment that occurs with a barriers of about 22 kcal/mol. According to the calculated results, we expect that the reaction is favored in acidic conditions and that the monoaquated complex should be the species reacting with DNA.
authors.affiliation: Dipartimento di Chimica Universita della Calabria,Via P. Bucci, cubo 14c, 87036 Arcavacata di Rende (CS), Centro di Calcolo ad Alte Prestazioni per Elaborazioni Parallele e Distribuite - Centro d'Eccellenza MIUR, Rende 87036, Italy.
authors.forename: Maria Fatima A
authors.initials: MF
authors.lastname: Lucas
authors.forename: Mateij
authors.initials: M
authors.lastname: Pavelka
authors.forename: Marta E
authors.initials: ME
authors.lastname: Alberto
authors.forename: Nino
authors.initials: N
authors.lastname: Russo
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry*; D016190:Carboplatin / Q000737:chemistry; D002945:Cisplatin / Q000737:chemistry; D003198:Computer Simulation; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D008024:Ligands; D008958:Models, Molecular; D009944:Organoplatinum Compounds / Q000737:chemistry*; D000077150:Oxaliplatin; D013816:Thermodynamics
chemical_list: D000970:Antineoplastic Agents; D008024:Ligands; D009944:Organoplatinum Compounds; D000077150:Oxaliplatin; D016190:Carboplatin; D002945:Cisplatin