Majcher Urszula, Klejborowska Greta, Kaik Magdalena, Maj Ewa, Wietrzyk Joanna, Moshari Mahshad, Preto Jordane, Tuszynski Jack A, Huczyński Adam
Department of Bioorganic Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Umultowska 89b, 61-614 Poznan, Poland.
Hirszfeld Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Rudolfa Weigla 12, 53-114 Wrocław, Poland.
Cells. 2018 Nov 19;7(11):216. doi: 10.3390/cells7110216.
Specific modifications of colchicine followed by synthesis of its analogues have been tested in vitro with the objective of lowering colchicine toxicity. Our previous studies have clearly shown the anticancer potential of double-modified colchicine derivatives in C-7 and C-10 positions. Here, a series of novel triple-modified colchicine derivatives is reported. They have been obtained following a four-step strategy. In vitro cytotoxicity of these compounds has been evaluated against four human tumor cell lines (A549, MCF-7, LoVo, and LoVo/DX). Additionally, the mode of binding of the synthesized compounds was evaluated in silico using molecular docking to a 3D structure of β-tubulin based on crystallographic data from the Protein Data Bank and homology methodology. Binding free energy estimates, binding poses, and MlogP values of the compounds were obtained. All triple-modified colchicine derivatives were shown to be active at nanomolar concentrations against three of the investigated cancer cell lines (A549, MCF-7, LoVo). Four of them also showed higher potency against tumor cells over normal cells as confirmed by their high selectivity index values. A vast majority of the synthesized derivatives exhibited several times higher cytotoxicity than colchicine, doxorubicin, and cisplatin.
为降低秋水仙碱的毒性，人们对秋水仙碱进行了特定修饰并合成了其类似物，且已在体外进行了测试。我们之前的研究清楚地表明了在C-7和C-10位双修饰秋水仙碱衍生物的抗癌潜力。在此，报道了一系列新型三修饰秋水仙碱衍生物。它们是通过四步策略获得的。已针对四种人类肿瘤细胞系（A549、MCF-7、LoVo和LoVo/DX）评估了这些化合物的体外细胞毒性。此外，基于蛋白质数据库的晶体学数据和同源方法，使用分子对接至β-微管蛋白的3D结构，在计算机上评估了合成化合物的结合模式。获得了化合物的结合自由能估计值、结合姿势和MlogP值。所有三修饰秋水仙碱衍生物在纳摩尔浓度下对三种被研究的癌细胞系（A549、MCF-7、LoVo）均表现出活性。其中四种还因其高选择性指数值而显示出对肿瘤细胞的效力高于正常细胞。绝大多数合成衍生物表现出比秋水仙碱、阿霉素和顺铂高几倍的细胞毒性。
