Lu Xiao-Yuan, Wang Zhong-Chang, Ren Shen-Zhen, Shen Fa-Qian, Man Ruo-Jun, Zhu Hai-Liang
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210023, People's Republic of China.
Bioorg Med Chem Lett. 2016 Aug 1;26(15):3491-8. doi: 10.1016/j.bmcl.2016.06.037. Epub 2016 Jun 16.
Cyclooxygenase-2 is frequently overexpression in malignant tumors and the product PGE2 promotes cancer cell progression and metastasis. We designed novel series of coumarin sulfonamides derivatives to improve biological activities of COX-2 inhibition and anticancer. Among them, compound 7t showed most powerful selective inhibitory and antiproliferative activity (IC50=0.09μM for COX-2, IC50=48.20μM for COX-1, IC50=0.36μM against HeLa cells), comparable to the control positive compound Celecoxib (0.31μM, 43.37μM, 7.79μM). Cancer cell apoptosis assay were performed and results indicated that compound 7t effectively fuels HeLa cells apoptosis in a dose and time-dependent manner. Moreover, 7t could significantly suppress cancer cell adhesion, migration and invasion which were essential process of cancer metastasis. Docking simulations results was further indicated that compound 7t could bind well to the COX-2 active site and guided a reasonable design of selective COX-2 inhibitor with anticancer activities in future.
环氧化酶-2在恶性肿瘤中经常过度表达，其产物前列腺素E2促进癌细胞的进展和转移。我们设计了一系列新型香豆素磺酰胺衍生物，以提高对环氧化酶-2的抑制和抗癌生物活性。其中，化合物7t表现出最强的选择性抑制和抗增殖活性（对环氧化酶-2的IC50 = 0.09μM，对环氧化酶-1的IC50 = 48.20μM，对人宫颈癌HeLa细胞的IC50 = 0.36μM），与对照阳性化合物塞来昔布（0.31μM，43.37μM，7.79μM）相当。进行了癌细胞凋亡检测，结果表明化合物7t以剂量和时间依赖性方式有效地促进HeLa细胞凋亡。此外，7t可以显著抑制癌细胞的粘附、迁移和侵袭，这些是癌症转移的重要过程。对接模拟结果进一步表明，化合物7t可以很好地结合到环氧化酶-2的活性位点，并为未来设计具有抗癌活性的选择性环氧化酶-2抑制剂提供合理指导。
