Pavelka Matej, Lucas Maria Fatima A, Russo Nino
Dipartimento di Chimica Università della Calabria, Via P. Bucci, cubo 14c, 87036 Arcavacata di Rende (CS), Italy.
Chemistry. 2007;13(36):10108-16. doi: 10.1002/chem.200700887.
The hydrolysis reaction mechanisms of carboplatin, a second-generation anticancer drug, have been explored by combining density functional theory (DFT) with the conductor-like dielectric continuum model (CPCM) approach. The 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. We 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. From the computed potential-energy surfaces it is established that the water hydrolysis takes place with an activation barrier of 30 kcal mol(-1), confirming the very slow reaction observed experimentally. The decomposition of carboplatin upon acidification was also investigated and we have computed a 21 kcal mol(-1) barrier to be overcome (experimental value 23 kcal mol(-1)). We 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 ring-opening reaction.
通过将密度泛函理论（DFT）与类导体介电连续模型（CPCM）方法相结合，对第二代抗癌药物卡铂的水解反应机理进行了探索。预计卡铂在水中的分解将通过双相机制进行，即先发生开环过程，随后丙二酸酯配体脱落。我们研究了该反应在水和酸性条件下的情况，并确定丙二酸酯配体中质子的数量对该体系的能量学有直接影响。对优化结构的仔细观察发现，在卡铂氨基附近存在一个必要的有序水分子。因此，我们还研究了该反应与一个明确水分子的情况。从计算出的势能面可知，水水解反应的活化能垒为30 kcal mol⁻¹，这证实了实验中观察到的反应非常缓慢。还研究了酸化后卡铂的分解情况，我们计算出需要克服的能垒为21 kcal mol⁻¹（实验值为23 kcal mol⁻¹）。我们还确定限速过程是第一次水合作用，并确定了靠近两个胺基的水分子在降低开环反应活化能垒方面的重要性。
