微管蛋白聚合抑制剂秋水仙碱衍生物的研究进展

Progress in the development of colchicine derivatives as tubulin polymerization inhibitors

微管是真核细胞骨架的重要组成部分,它由α和β微管蛋白异二聚体聚合形成,在细胞有丝分裂中具有非常重要的作用。因此,微管成为抗癌药物的重要靶点之一,微管蛋白抑制剂也成为一类有效的抗癌药物。秋水仙碱是典型的微管蛋白聚合抑制剂,但由于不良反应大,限制了其作为抗肿瘤药物在临床的应用。近年来,对秋水仙碱的结构修饰主要集中在C环的10位和B环的7位侧链,包括C环10位的甲氧基被脂肪胺、芳香胺、巯基衍生物取代、B环7位的乙酰氨基被各种酰胺置换,以及在C_(10)位和C_7位同时修饰。本文主要介绍近5年来秋水仙碱结构修饰的研究进展。

Microtubules are heterodimers formed by the polymerization of a-and/3-tubulins. They are the vital components of cytoskeleton in eukaryotic cells and play a key role in cell cycles and mitosis. Therefore, microtubule is one of the most important targets for the development of new anti-cancer drugs, and tubulin inhibitors are effective anti-cancer drugs. Colchicine is one of the typical tubulin polymerization inhibitors. However, its clinical applications as an anti-cancer drug are limited by its severe toxicity. In recent years, the structure modifications of colchicine are mainly made at its C10 position of the C-ring, C7 position of the B-ring. The C10 methoxy group had been replaced by aliphatic or aromatic aminesthiol groups. Likewise, the acetamide group at the C7 position had aiso been replaced by a variety of amides, resulting in some doubletarget molecules. In addition, structural modifications at both the C10 and C7 positions had also been made. In this review, we mainly summarize the developments of colchicine derivatives in recent five years.