Department of Medical Chemistry, Faculty of Chemistry, Adam Mickiewicz University, Uniwersytetu Poznańskiego 8, 61-614, Poznań, Poland; TriMen Chemicals, Piłsudskiego 141, 92-318, Łódź, Poland.
Department of Oncology, University of Alberta, Edmonton, T6G 1Z2, Canada.
Eur J Med Chem. 2021 Apr 5;215:113282. doi: 10.1016/j.ejmech.2021.113282. Epub 2021 Feb 10.
Colchicine shows very high antimitotic activity, therefore, it is used as a lead compound for generation of new anticancer agents. In the hope of developing novel, useful drugs with more favourable pharmacological profiles, a series of doubly modified colchicine derivatives has been designed, synthesized and characterized. These novel carbamate or thiocarbamate derivatives of 10-demethoxy-10-methylaminocolchicine have been tested for their antiproliferative activity against four human cancer cell lines. Additionally, their mode of action has been evaluated as colchicine binding site inhibitors, using molecular docking studies. Most of the tested compounds showed greater cytotoxicity (IC in a low nanomolar range) and were characterized by a higher selectivity index than standard chemotherapeutics such as cisplatin and doxorubicin as well as unmodified colchicine. Their pharmacological use in cancer therapy could possibly be accomplished with lower dosages and result in less acute toxicity problems than in the case of colchicine. In addition, we present a QSAR model for predicting the antiproliferative activity of doubly modified derivatives for two tumour cell lines.
秋水仙碱具有非常高的抗有丝分裂活性，因此被用作生成新型抗癌药物的先导化合物。为了开发具有更有利的药理学特性的新型有用药物，设计、合成并表征了一系列双修饰的秋水仙碱衍生物。已经测试了这些新型的 10-去甲氧基-10-甲基氨基秋水仙碱的氨基甲酸酯或硫代氨基甲酸酯衍生物对四种人癌细胞系的增殖活性。此外，还通过分子对接研究评估了它们作为秋水仙碱结合位点抑制剂的作用模式。大多数测试的化合物表现出更强的细胞毒性（在低纳摩尔范围内的 IC 值），并且与顺铂和阿霉素等标准化疗药物以及未修饰的秋水仙碱相比，具有更高的选择性指数。与秋水仙碱相比，它们在癌症治疗中的药理学用途可能需要更低的剂量，并导致更少的急性毒性问题。此外，我们还提出了一个 QSAR 模型，用于预测两种肿瘤细胞系的双修饰衍生物的增殖活性。
