Department of Chemistry and Center for Gene Regulation in Health and Disease, College of Sciences & Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
Eur J Med Chem. 2012 Oct;56:17-29. doi: 10.1016/j.ejmech.2012.08.005. Epub 2012 Aug 10.
Cyclooxygenase (COX) inhibitors Indomethacin and its structural analogs Sulindac exhibit cell growth inhibition and apoptosis inducing activities in various cancer cell lines via COX independent mechanisms. In this study, the molecular structures of Indomethacin and Sulindac were used as starting scaffolds to design novel analogs and their effects on the proliferation of human cancer cells were evaluated. Compared to Indomethacin and Sulindac inhibiting cancer cell proliferation with IC(50)s of more than 1 mM, the derivatives displayed significantly increased activities. Especially, one of the Indomethacin analogs inhibited the growth of a series of cancer cell lines with IC(50)s around 0.5 μM-3 μM. Mechanistic investigation revealed that the new analog was in fact a tubulin inhibitor, although the parental compound Indomethacin did not show any tubulin inhibitory activity. Tubulin polymerization assay indicated this compound inhibited tubulin assembly at high concentrations, but promoted this process at low concentrations which is a very unique mechanism. The binding mode of this compound in tubulin was predicted using the molecular docking simulation.
环氧化酶 (COX) 抑制剂吲哚美辛及其结构类似物舒林酸通过 COX 非依赖性机制在各种癌细胞系中表现出细胞生长抑制和诱导细胞凋亡的活性。在本研究中，将吲哚美辛和舒林酸的分子结构用作起始支架来设计新型类似物，并评估它们对人癌细胞增殖的影响。与吲哚美辛和舒林酸抑制癌细胞增殖的 IC50 大于 1mM 相比，这些衍生物表现出显著增强的活性。特别是，一种吲哚美辛类似物以约 0.5μM-3μM 的 IC50 抑制一系列癌细胞系的生长。机制研究表明，尽管母体化合物吲哚美辛没有表现出任何微管蛋白抑制活性，但这种新类似物实际上是一种微管蛋白抑制剂。微管蛋白聚合测定表明，该化合物在高浓度时抑制微管蛋白组装，但在低浓度时促进该过程，这是一种非常独特的机制。使用分子对接模拟预测了该化合物在微管蛋白中的结合模式。
