Wexselblatt Ezequiel, Raveendran Raji, Salameh Sawsan, Friedman-Ezra Aviva, Yavin Eylon, Gibson Dan
Institute for Drug Research, School of Pharmacy, The Hebrew University, Jerusalem, 91120 (Israel).
Chemistry. 2015 Feb 9;21(7):3108-14. doi: 10.1002/chem.201405467. Epub 2014 Dec 21.
The design of Pt(IV) pro-drugs as anticancer agents is predicated on the assumption that they will not undergo substitution reactions before entering the cancer cell. Attempts to improve the cytotoxic properties of Pt(IV) pro-drugs included the use of haloacetato axial ligands. Herein, we demonstrate that Pt(IV) complexes with trifluoroacetato (TFA) or dichloroacetato (DCA) ligands can be unstable under biologically relevant conditions and readily undergo hydrolysis, which results in the loss of the axial TFA or DCA ligands. The half-lives for Pt(IV) complexes with two TFA or DCA ligands at pH 7 and 37 °C range from 6 to 800 min, which is short relative to the duration of cytotoxicity experiments that last 24-96 h. However, complexes with two monochloroacetato (MCA) or acetato axial ligands are stable under biologically relevant conditions. The loss of the axial ligands depends primarily on the electron-withdrawing strength of the axial ligands, but also upon the nature of the equatorial ligands. We were unable to find obvious correlations between the structures of the Pt(IV) complexes and the rates of decay of the parent compounds. The X-ray crystal structures of the bis-DCA and bis-MCA Pt(IV) derivatives of oxaliplatin did not reveal any significant structural differences that could explain the observed differences in stability.
将铂（IV）前药设计为抗癌剂的前提是假设它们在进入癌细胞之前不会发生取代反应。改善铂（IV）前药细胞毒性的尝试包括使用卤代乙酸轴向配体。在此，我们证明了含有三氟乙酸根（TFA）或二氯乙酸根（DCA）配体的铂（IV）配合物在生物学相关条件下可能不稳定，并容易发生水解，这会导致轴向TFA或DCA配体的丢失。在pH 7和37°C条件下，含有两个TFA或DCA配体的铂（IV）配合物的半衰期为6至800分钟，相对于持续24 - 96小时的细胞毒性实验持续时间而言较短。然而，含有两个一氯乙酸根（MCA）或乙酸根轴向配体的配合物在生物学相关条件下是稳定的。轴向配体的丢失主要取决于轴向配体的吸电子强度，但也取决于赤道配体的性质。我们未能在铂（IV）配合物的结构与母体化合物的衰变速率之间找到明显的相关性。奥沙利铂的双DCA和双MCA铂（IV）衍生物的X射线晶体结构未显示出任何能解释所观察到的稳定性差异的显著结构差异。
