Indomethacin derivatives as tubulin stabilizers to inhibit cancer cell proliferation. Issue 2 (15th January 2016)

• Record Type: Journal Article
• Authors: Chennamaneni, Snigdha; Gan, Chunfang; Lama, Rati; Zhong, Bo; Su, Bin
• Is Part Of: Bioorganic & medicinal chemistry. Volume 24:Issue 2(2016)
• Page Start: 277
• Page End: 285
• Publication Date: 2016-01-15
• Subjects: COX cyclooxygenase -- NSAIDs non-steroidal anti-inflammatory drugs -- SAR structure activity relationship -- DCC N, N′-dicyclohexylcarbodiimide -- PyBOP benzotriazol-1-yl-oxytripyrrolidinophosphonium hexafluorophosphate; COX inhibitor -- Indomethacin -- Tubulin -- Cancer; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2015.12.016
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: Cyclooxygenase (COX) inhibitor Indomethacin analogs exhibited more potent cancer cell growth inhibition and apoptosis inducing activities than the parental compound. The anti-proliferative mechanism investigation of the analogs revealed that they inhibited tubulin polymerization at high concentrations whereas enhanced polymerization at low concentrations. The two opposite activities might antagonize each other and impaired the anti-proliferative activity of the derivatives eventually. In this study, we further performed lead optimization based on the structure activity relationship (SAR) generated. One of the new Indomethacin derivatives compound11 {2-(4-(benzyloxy)phenyl)- N -(1-(4-bromobenzoyl)-3-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-2-methyl-1 H -indol-5-yl)acetamide} inhibited the proliferation of a panel of cancer cell lines with IC50 s at the sub-micromole levels. Further study revealed that the compound only enhanced tubulin polymerization and was a tubulin stabilizer.