Laboratoire Chrono-environnement (UMR CNRS 6249), Université de Franche-Comté, 16 route de Gray, 25030 Besançon, France.
Metallomics. 2019 Apr 17;11(4):833-844. doi: 10.1039/c8mt00371h.
Interaction of platinum-based drugs with proteins containing sulphur amino acids is usually argued as one of the major reasons for the observed resistance to these drugs, mainly due to the deactivation of the native compounds by very efficient thiolation processes in the organism. In this work, we have investigated the detailed thermodynamics and kinetics of reaction between cisplatin cis-[PtCl2(NH3)2] and its major hydrolysed forms (monohydroxocisplatin cis-[PtCl(OH)(NH3)2] and monoaquacisplatin cis-[PtCl(H2O)(NH3)2]+) with various thiolates (methanethiolate, cysteine and glutathione) and methionine. We have used a demanding quantum chemistry approach at the MP2 and DFT levels of theory to determine the Gibbs free energies and the barrier of reactions of the most possible reaction paths. The substitution of the four ligands of the complexes studied here (Cl-, OH-, H2O and NH3) can either proceed by direct thiolations or bidentations. Our Raman spectroscopy measurements show that only two thiolations actually occur, although four are possible in principle. The reason could lie in the bidentation reactions eventually taking place after each thiolation, which is backed up by our computational results. The observed lability scale of the ligands under thiolate exposure was found to be in the following order H2O > Cl- ≈ NH3(trans) > NH3(cis) > OH-, the difference between ammine ligands being induced by a significant trans-labilization by thiolates. Finally, the S,N bidentation is shown to be preferred with respect to the S,O one.
铂类药物与含硫氨基酸的蛋白质相互作用通常被认为是导致这些药物观察到的耐药性的主要原因之一，主要是由于生物体中非常有效的硫醇化过程使天然化合物失活。在这项工作中，我们研究了顺铂 cis-[PtCl2(NH3)2]及其主要水解形式（单羟顺铂 cis-[PtCl(OH)(NH3)2]和单水合顺铂 cis-[PtCl(H2O)(NH3)2]+）与各种硫醇化物（甲硫醇、半胱氨酸和谷胱甘肽）和蛋氨酸之间的详细热力学和动力学反应。我们使用了苛刻的量子化学方法，即在 MP2 和 DFT 理论水平上，确定了最可能反应途径的吉布斯自由能和反应势垒。研究中配合物的四个配体（Cl-、OH-、H2O 和 NH3）的取代可以通过直接硫醇化或双配位进行。我们的拉曼光谱测量表明，虽然理论上可以进行四种取代，但实际上只发生了两种取代。原因可能在于每个硫醇化后最终发生的双配位反应，这得到了我们计算结果的支持。在硫醇暴露下观察到的配体不稳定性顺序为 H2O > Cl- ≈ NH3(trans) > NH3(cis) > OH-，由于硫醇的显著反位活化，导致氨配体之间存在差异。最后，显示 S,N 双配位优先于 S,O 双配位。
