Boček Ida, Hok Lucija, Persoons Leentje, Daelemans Dirk, Vianello Robert, Hranjec Marijana
Department of Organic Chemistry, Faculty of Chemical Engineering and Technology, University of Zagreb, Zagreb, Croatia.
Laboratory for the Computational Design and Synthesis of Functional Materials, Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Zagreb, Croatia.
Bioorg Chem. 2022 Oct;127:106032. doi: 10.1016/j.bioorg.2022.106032. Epub 2022 Jul 16.
Imidazo[4,5-b]pyridine derived acrylonitriles were synthesized and explored for their in vitro antiproliferative effect on a diverse human cancer cell line panel. Three compounds, 20, 21 and 33, showed strong activity in the submicromolar range (IC 0.2-0.6 μM), and were chosen for further biological experiments. Immunofluorescence staining and tubulin polymerization assays confirmed tubulin as the main target, but excluded its colchicine-binding site as a potential interacting unit. This was supported by the computational analysis, which revealed that the most potent ligands act on the extended colchicine site on the surface between interacting tubulin subunits, where they interfere with their polymerization and reveal pronounced antitumor properties. In addition, lead molecule 21 potently inhibited cancer cell migration, while it did not affect the viability of normal cells even at the highest concentration tested (100 µM).
合成了咪唑并[4,5 - b]吡啶衍生的丙烯腈，并研究了它们对多种人类癌细胞系的体外抗增殖作用。三种化合物20、21和33在亚微摩尔范围内表现出较强活性（IC 0.2 - 0.6 μM），并被选用于进一步的生物学实验。免疫荧光染色和微管蛋白聚合试验证实微管蛋白是主要靶点，但排除了其秋水仙碱结合位点作为潜在的相互作用单元。这得到了计算分析的支持，该分析表明最有效的配体作用于相互作用的微管蛋白亚基之间表面上的扩展秋水仙碱位点，在那里它们干扰微管蛋白的聚合并显示出明显的抗肿瘤特性。此外，先导分子21强烈抑制癌细胞迁移，而即使在测试的最高浓度（100 μM）下，它也不影响正常细胞的活力。
