The second-generation anticancer drug Nedaplatin: a theoretical investigation on the hydrolysis mechanism.
The hydrolysis reaction processes of the second-generation platinum derivative Nedaplatin have been studied using density functional theory (DFT) combined with the conductor-like dielectric continuum model (CPCM) approach, in order to obtain detailed data on its mechanism of action. The first and the second hydrolysis of Nedaplatin, corresponding to the ring opening followed by the loss of the ligand, respectively, have been explored in neutral and acid conditions. The influence of an extra water molecule which could assist the degradation processes has also been considered including in our models an explicit water molecule other than the reactive one. The computed potential energy surfaces show that the rate limiting step in neutral conditions is the first hydrolysis process and, consequently, the double hydrated complex is suggested to be the species reacting with the DNA purine bases, while in acid conditions the trend is different, with the second hydrolysis process being the rate limiting step. The results obtained in this work allow us to make a comparison with the trends previously found for the other platinum anticancer drugs currently used in the medical protocols.
Dipartimento di Chimica, Università 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, Italy.
Marta E
ME
Alberto
Maria Fatima A
MF
Lucas
Matej
M
Pavelka
Nino
N
Russo
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D006868:Hydrolysis; D009944:Organoplatinum Compounds / Q000737:chemistry* / Q000378:metabolism; D013816:Thermodynamics
D000970:Antineoplastic Agents; D009944:Organoplatinum Compounds; C053989:nedaplatin