Department of Chemistry, National University of Singapore, 3 Science Drive 3, 117543 Singapore.
J Med Chem. 2012 Sep 13;55(17):7571-82. doi: 10.1021/jm300580y. Epub 2012 Aug 24.
Platinum(II) anticancer drug cisplatin is one of the most important chemotherapeutic agents in clinical use but is limited by its high toxicity and severe side effects. Platinum(IV) anticancer prodrugs can overcome these limitations by resisting premature aquation and binding to essential plasma proteins. Structure-activity relationship studies revealed a link between the efficacy of platinum(IV) complexes with the nature of their axial ligands, which can be modified to enhance the properties of the prodrug. The existing paradigm of employing platinum(IV) complexes with symmetrical axial carboxylate ligands does not fully exploit their vast potential. A new approach was conceived to control properties of platinum(IV) prodrugs using contrasting axial ligands via sequential acylation. We report a novel class of asymmetric platinum(IV) carboxylates based on the cisplatin template containing both hydrophilic and lipophilic ligands on the same scaffold designed to improve their aqueous properties and enhance their efficacy against cancer cells in vitro.
铂(II)抗癌药物顺铂是临床应用中最重要的化疗药物之一，但由于其毒性高和严重的副作用而受到限制。铂(IV)抗癌前药可以通过抵抗过早水合和与必需的血浆蛋白结合来克服这些限制。构效关系研究表明，铂(IV)配合物的功效与其轴向配体的性质之间存在联系，通过修饰这些配体可以增强前药的性质。目前采用具有对称轴向羧酸盐配体的铂(IV)配合物的范例并没有充分发挥它们的巨大潜力。通过顺序酰化，我们设想了一种使用对比轴向配体控制铂(IV)前药性质的新方法。我们报告了一类新型的基于顺铂模板的不对称铂(IV)羧酸酯，它们在同一支架上同时含有亲水和亲脂性配体，旨在改善它们的水性质并增强它们对体外癌细胞的疗效。
