Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614 Poznan, Poland.
Department of Biochemistry and Molecular Biology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, United States.
Bioorg Chem. 2020 Apr;97:103664. doi: 10.1016/j.bioorg.2020.103664. Epub 2020 Feb 13.
Colchicine belongs to a large group of microtubule polymerization inhibitors. Although the anti-cancer activity of colchicine and its derivatives has been established, none of them has found commercial application in cancer treatment due to side effects. Therefore, we designed and synthesized a series of six triple-modified 4-chlorothiocolchicine analogues with amide moieties and one urea derivative. These novel derivatives were tested against several different cancer cell lines (A549, MCF-7, LoVo, LoVo/DX) and primary acute lymphoblastic leukemia (ALL) cells and they showed activity in the nanomolar range. The obtained IC values for novel derivatives were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies of colchicine and selected analogues were undertaken to indicate that they induced apoptotic cell death in ALL-5 cells. We also performed in silico studies to predict binding modes of the 4-chlorothiocolchicine derivatives to different β tubulin isotypes. The results indicate that select triple-modified 4-chlorothiocolchicine derivatives represent highly promising novel cancer chemotherapeutics.
秋水仙素属于一大类微管聚合抑制剂。虽然秋水仙素及其衍生物的抗癌活性已得到证实,但由于副作用,它们都没有在癌症治疗中得到商业应用。因此,我们设计并合成了一系列带有酰胺部分和一个脲衍生物的 6 种三重修饰的 4-氯硫代秋水仙碱类似物。这些新型衍生物在几种不同的癌细胞系(A549、MCF-7、LoVo、LoVo/DX)和急性淋巴细胞白血病(ALL)细胞中进行了测试,结果显示其在纳摩尔范围内具有活性。与未修饰的秋水仙素和常见的抗癌药物如阿霉素和顺铂相比,新型衍生物的 IC 值更低。进一步研究了秋水仙素和选定的类似物,表明它们在 ALL-5 细胞中诱导了细胞凋亡。我们还进行了计算机模拟研究,以预测 4-氯硫代秋水仙碱衍生物与不同β微管蛋白同工型的结合模式。结果表明,选择三重修饰的 4-氯硫代秋水仙碱衍生物代表了极有前途的新型癌症化疗药物。