Title

Indomethacin Derivatives as Tubulin Stabilizers to Inhibit Cancer Cell Proliferation

Document Type

Article

Publication Date

1-15-2016

Publication Title

Bioorganic & Medicinal Chemistry

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.

Comments

This research was supported by a Faculty Research Development (FRD) grant from Cleveland State University, Center for Gene Regulation in Health and Disease (GRHD) of Cleveland State University and Ohio Department of Development (ODOD), and National Science Foundation Major Research Instrumentation Grants (CHE-0923398 and CHE-1126384).

DOI

10.1016/j.bmc.2015.12.016

Volume

24

Issue

2