Department of Experimental and Clinical Pharmacology, Pomeranian Medical University in Szczecin, Powstanców Wielkopolskich 72, 70-111 Szczecin, Poland.
Department of Organic and Physical Chemistry, Faculty of Chemical Technology and Engineering, West Pomeranian University of Technology, Szczecin, Al. Piastów 42, 71-065 Szczecin, Poland.
Int J Mol Sci. 2021 Feb 28;22(5):2462. doi: 10.3390/ijms22052462.
Most anticancer drugs target mitosis as the most crucial and fragile period of rapidly dividing cancer cells. However the limitations of classical chemotherapeutics drive the search for new more effective and selective compounds. For this purpose structural modifications of the previously characterized pyridine aalog () were incorporated aiming to obtain an antimitotic inhibitor of satisfactory and specific anticancer activity. Structure-activity relationship analysis of the compounds against a panel of cancer cell lines allowed to select a compound with a thiophene ring at C5 of a 3,4-dihydropyridine-2(1)-thione () with promising antiproliferative activity (IC equal 1.71 ± 0.58 µM) and selectivity (SI = 21.09) against melanoma A375 cells. Moreover, all three of the most active compounds from the antiproliferative study, namely , and showed better selectivity against A375 cells than reference drug, suggesting their possible lower toxicity and wider therapeutic index. As further study revealed, selected compounds inhibited tubulin polymerization via colchicine binding site in dose dependent manner, leading to aberrant mitotic spindle formation, cell cycle arrest and apoptosis. Summarizing, the current study showed that among obtained mitotic-specific inhibitors analogue with thiophene ring showed the highest antiproliferative activity and selectivity against cancer cells.
大多数抗癌药物都将有丝分裂作为快速分裂癌细胞的最关键和最脆弱的时期作为靶点。然而，经典化疗药物的局限性促使人们寻找新的更有效和选择性的化合物。为此，对先前表征的吡啶类似物（）进行了结构修饰，旨在获得具有令人满意和特异性抗癌活性的抗有丝分裂抑制剂。对一系列癌细胞系的化合物进行构效关系分析，选择了一种具有噻吩环的 3,4-二氢吡啶-2(1)-硫酮（）的化合物，该化合物具有有前途的增殖活性（IC 值为 1.71 ± 0.58 µM）和选择性（SI = 21.09）针对黑色素瘤 A375 细胞。此外，在增殖研究中最活跃的三种化合物，即、和，对 A375 细胞的选择性均优于参考药物，表明它们可能毒性更低，治疗指数更广。进一步研究表明，所选化合物通过秋水仙碱结合位点以剂量依赖的方式抑制微管聚合，导致有丝分裂纺锤体形成异常、细胞周期停滞和细胞凋亡。总之，本研究表明，在所获得的有丝分裂特异性抑制剂类似物中，带有噻吩环的类似物表现出最高的抗癌细胞增殖活性和选择性。
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