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Indomethacin derivatives as tubulin stabilizers to inhibit cancer cell proliferation
Affiliation:1. Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA;2. College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning 530001, China;3. Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA;1. Institute of Organic Chemistry and Biochemistry, Gilead Sciences Research Center & IOCB, Academy of Sciences of the Czech Republic, Flemingovo nám. 2, 166 10 Praha 6, Czech Republic;2. School of Chemistry, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse St., Dublin 2, Ireland;3. Instituto de Química Médica, CSIC, Juan de la Cierva, 3, E-28006 Madrid, Spain;1. Department of Medicine DIMED, University of Padova, Via Giustiniani 2, 35128 Padova, Italy;2. Venetian Institute of Molecular Medicine, Padova, Italy;1. State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro-products, Ningbo University, Ningbo, Zhejiang, 315211, China;2. Key Laboratory of Chemical Biology and Traditional Chinese Medicine Research (Ministry of Education), College of Chemistry and Chemical Engineering, Hunan Normal University, Changsha, 410081, China;1. Department of Respiratory and Critical Care Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China;2. Analytical & Testing Center, Sichuan University, Chengdu, 610064, China;3. Targeted Tracer Research and Development Laboratory, Institute of Respiratory Health, Frontiers Science Center for Disease-related Molecular Network, West China Hospital, Sichuan University, Chengdu, Sichuan, 610064, China;4. Core Facility of West China Hospital, Sichuan University, Chengdu, Sichuan, 610041, China
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 compound 11 {2-(4-(benzyloxy)phenyl)-N-(1-(4-bromobenzoyl)-3-(2-((2-(dimethylamino)ethyl)amino)-2-oxoethyl)-2-methyl-1H-indol-5-yl)acetamide} inhibited the proliferation of a panel of cancer cell lines with IC50s at the sub-micromole levels. Further study revealed that the compound only enhanced tubulin polymerization and was a tubulin stabilizer.
Keywords:COX inhibitor  Indomethacin  Tubulin  Cancer
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