title: Indomethacin derivatives as tubulin stabilizers to inhibit cancer cell proliferation.
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.
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
authors.forename: Snigdha
authors.initials: S
authors.lastname: Chennamaneni
authors.affiliation: College of Chemistry and Materials Science, Guangxi Teachers Education University, Nanning 530001, China.
authors.forename: Chunfang
authors.initials: C
authors.lastname: Gan
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
authors.forename: Rati
authors.initials: R
authors.lastname: Lama
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA.
authors.forename: Bo
authors.initials: B
authors.lastname: Zhong
authors.affiliation: Department of Chemistry, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA; Center for Gene Regulation in Health and Disease, College of Sciences and Health Professions, Cleveland State University, 2121 Euclid Ave., Cleveland, OH 44115, USA. Electronic address: b.su@csuohio.edu.
authors.forename: Bin
authors.initials: B
authors.lastname: Su
mesh_terms: D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007213:Indomethacin / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D055550:Protein Stability / Q000187:drug effects; D013329:Structure-Activity Relationship; D014404:Tubulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D014404:Tubulin; D007213:Indomethacin
keywords: COX inhibitor; Cancer; Indomethacin; Tubulin