Abstract

A potential microtubule destabilising series of new indolizine derivatives was synthesised and tested for their anticancer activity against a panel of 60 human cancer cell lines. Compounds 11a, 11b, 15a, and 15j showed a broad spectrum of growth inhibitory activity against cancer cell lines representing leukaemia, melanoma and cancer of lung, colon, central nervous system, ovary, kidney, breast, and prostate. Among them, compound 11a was distinguishable by its excellent cytostatic activity, showing GI₅₀ values in the range of 10–100 nM on 43 cell lines. The less potent compounds 15a and 15j in terms of GI₅₀ values showed a high cytotoxic effect against tested colon cancer, CNS cancer, renal cancer and melanoma cell lines and only on few cell lines from other types of cancer. In vitro assaying revealed tubulin polymerisation inhibition by all active compounds. Molecular docking showed good complementarity of active compounds with the colchicine binding site of tubulin.

 抽象的

合成了一系列潜在的微管不稳定新型中氮茚衍生物，并测试了它们对 60 种人类癌细胞系的抗癌活性。化合物11a 、 11b 、 15a和15j对代表白血病、黑色素瘤和肺癌、结肠癌、中枢神经系统癌、卵巢癌、肾癌、乳腺癌和前列腺癌的癌细胞系表现出广谱的生长抑制活性。其中，化合物11a以其优异的细胞抑制活性而著称，在 43 种细胞系上显示 GI ₅₀值在 10-100 nM 范围内。就GI ₅₀值而言效力较低的化合物15a和15j显示出针对所测试的结肠癌、CNS癌症、肾癌和黑色素瘤细胞系的高细胞毒性作用，并且仅对来自其他类型癌症的少数细胞系具有高细胞毒性作用。体外测定显示所有活性化合物均抑制微管蛋白聚合。分子对接显示活性化合物与微管蛋白秋水仙碱结合位点具有良好的互补性。