Department of Medical 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 Med Chem. 2021 Feb 15;32:116014. doi: 10.1016/j.bmc.2021.116014. Epub 2021 Jan 11.
Colchicine is a plant alkaloid with a broad spectrum of biological and pharmacological properties. It has found application as an anti-inflammatory agent and also shows anticancer effects through its ability to destabilize microtubules by preventing tubulin dimers from polymerizing leading to mitotic death. However, adverse side effects have so far restricted its use in cancer therapy. This has led to renewed efforts to identify less toxic derivatives. In this article, we describe the synthesis of a set of novel double- and triple-modified colchicine derivatives. These derivatives were tested against primary acute lymphoblastic leukemia (ALL-5) cells and several established cancer cell lines including A549, MCF-7, LoVo and LoVo/DX. The novel derivatives were active in the low nanomolar range, with 7-deacetyl-10-thiocolchicine analogues more potent towards ALL-5 cells while 4-iodo-7-deacetyl-10-thiocolchicine analogues slightly more effective towards the LoVo cell line. Moreover, most of the synthesized compounds showed a favorable selectivity index (SI), particularly for ALL-5 and LoVo cell lines. Cell cycle analysis of the most potent molecules on ALL-5 and MCF-7 cell lines revealed contrasting effects, where M-phase arrest was observed in MCF-7 cells but not in ALL-5 cells. Molecular docking studies of all derivatives to the colchicine-binding site were performed and it was found that five of the derivatives showed strong β-tubulin binding energies, lower than -8.70 kcal/mol, while the binding energy calculated for colchicine is -8.09 kcal/mol. The present results indicate that 7-deacetyl-10-thiocolchicine and 4-iodo-7-deacetyl-10-thiocolchicine analogues constitute promising lead compounds as chemotherapy agents against several types of cancer.
秋水仙碱是一种具有广泛生物和药理活性的植物生物碱。它已被用作抗炎剂，并且通过阻止微管蛋白二聚体聚合导致有丝分裂死亡来破坏微管，从而显示出抗癌作用。然而，不良的副作用迄今为止限制了其在癌症治疗中的应用。这导致了重新努力寻找毒性较小的衍生物。在本文中，我们描述了一组新型双修饰和三修饰秋水仙碱衍生物的合成。这些衍生物针对原代急性淋巴细胞白血病（ALL-5）细胞和几种已建立的癌细胞系（包括 A549、MCF-7、LoVo 和 LoVo/DX）进行了测试。新型衍生物在低纳摩尔范围内具有活性，7-脱乙酰-10-硫代秋水仙碱类似物对 ALL-5 细胞更有效，而 4-碘-7-脱乙酰-10-硫代秋水仙碱类似物对 LoVo 细胞系略有效。此外，大多数合成化合物表现出良好的选择性指数（SI），特别是对 ALL-5 和 LoVo 细胞系。对 ALL-5 和 MCF-7 细胞系上最有效分子的细胞周期分析显示出相反的作用，其中 M 期阻滞在 MCF-7 细胞中观察到，但在 ALL-5 细胞中未观察到。对所有衍生物到秋水仙碱结合位点的分子对接研究表明，五种衍生物显示出与β-微管蛋白结合的强结合能，低于-8.70 kcal/mol，而计算出的秋水仙碱结合能为-8.09 kcal/mol。目前的结果表明，7-脱乙酰-10-硫代秋水仙碱和 4-碘-7-脱乙酰-10-硫代秋水仙碱类似物构成有前途的先导化合物，可作为针对多种类型癌症的化疗药物。
