Laboratory of Organic and Medicinal Chemistry, Department of Pharmaceutical Sciences and Natural Products, Central University of Punjab, Bathinda, Punjab 151001, India.
Laboratory of Molecular Medicine, Department of Human Genetics and Molecular Medicines, Central University of Punjab, Bathinda, Punjab 151001, India.
Bioorg Chem. 2018 Aug;78:130-140. doi: 10.1016/j.bioorg.2018.02.027. Epub 2018 Feb 28.
A number of pyrimidine bridged combretastatin derivatives were designed, synthesized and evaluated for anticancer activities against breast cancer (MCF-7) and lung cancer (A549) cell lines using MTT assays. Most of the synthesized compounds displayed good anticancer activity with IC values in low micro-molar range. Compounds 4a and 4p were found most potent in the series with IC values of 4.67 µM & 3.38 µM and 4.63 µM & 3.71 µM against MCF7 and A549 cancer cell lines, respectively. Biological evaluation of these compounds showed that selective cancer cell toxicity (in vitro using human lung and breast cancer cell lines) might be due to the inhibition of antioxidant enzymes instigating elevated ROS levels which triggers intrinsic apoptotic pathways. These compounds were found nontoxic to the normal human primary cells. Compound 4a, was found to be competitive inhibitor of colchicine and in the tubulin binding assay it showed tubulin polymerization inhibition potential comparable to colchicine. The molecular modeling studies also showed that the synthesized compounds fit well in the colchicine-binding pocket.
设计、合成了一系列嘧啶桥联康普瑞汀衍生物，并通过 MTT 法评估了它们对乳腺癌（MCF-7）和肺癌（A549）细胞系的抗癌活性。大多数合成化合物表现出良好的抗癌活性，IC 值在低微摩尔范围内。化合物 4a 和 4p 在该系列中表现出最强的活性，对 MCF7 和 A549 癌细胞系的 IC 值分别为 4.67 µM 和 3.38 µM，以及 4.63 µM 和 3.71 µM。这些化合物的生物学评价表明，选择性的癌细胞毒性（体外用人肺和乳腺癌细胞系）可能是由于抗氧化酶的抑制导致 ROS 水平升高，从而触发内在的凋亡途径。这些化合物对正常的人原代细胞没有毒性。化合物 4a 被发现是秋水仙碱的竞争性抑制剂，在微管蛋白结合试验中，它显示出与秋水仙碱相当的微管蛋白聚合抑制潜力。分子模拟研究还表明，合成的化合物很好地适合秋水仙碱结合口袋。
