The hydrolysis reaction mechanisms of carboplatin, a secondgeneration anticancer drug, have been explored by combining density functional theory (DFT) with the conductor- like dielectric continuum model (CPCM) approach.T he decomposition of carboplatin in water is expected to take place through a biphasic mechanism with a ring-opening process followed by the loss of the malonato ligand.W e have investigated this reaction in water and acid conditions and established that the number of protons present in the malonato ligand has a direct effect on the energetics of this system.Close observation of the optimised structures revealed a necessary systematic water molecule in the vicinity of the amino groups of carboplatin. For this reason we have also investigated this reaction with an explicit water molecule.F rom the computed potential- energy surfaces it is established that the water hydrolysis takes place with an activation barrier of 30 kcalmol1, confirming the very slow reaction observed experimentally.T he decomposition of carboplatin upon acidification was also investigated and we have computed a 21 kcalmol1 barrier to be overcome (experimental value 23 kcalmol1).W e have also established that the rate-limiting process is the first hydration, and ascertained the importance of a water molecule close to the two amine groups in lowering the activation barriers for the ringopening reaction.
On the Hydrolysis Mechanism of the Second-Generation Anticancer Drug Carboplatin
RUSSO, Nino
2007-01-01
Abstract
The hydrolysis reaction mechanisms of carboplatin, a secondgeneration anticancer drug, have been explored by combining density functional theory (DFT) with the conductor- like dielectric continuum model (CPCM) approach.T he decomposition of carboplatin in water is expected to take place through a biphasic mechanism with a ring-opening process followed by the loss of the malonato ligand.W e have investigated this reaction in water and acid conditions and established that the number of protons present in the malonato ligand has a direct effect on the energetics of this system.Close observation of the optimised structures revealed a necessary systematic water molecule in the vicinity of the amino groups of carboplatin. For this reason we have also investigated this reaction with an explicit water molecule.F rom the computed potential- energy surfaces it is established that the water hydrolysis takes place with an activation barrier of 30 kcalmol1, confirming the very slow reaction observed experimentally.T he decomposition of carboplatin upon acidification was also investigated and we have computed a 21 kcalmol1 barrier to be overcome (experimental value 23 kcalmol1).W e have also established that the rate-limiting process is the first hydration, and ascertained the importance of a water molecule close to the two amine groups in lowering the activation barriers for the ringopening reaction.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
