4.7 Article

Synthesis and biological evaluation of podophyllotoxin congeners as tubulin polymerization inhibitors

期刊

BIOORGANIC & MEDICINAL CHEMISTRY
卷 22, 期 19, 页码 5466-5475

出版社

PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmc.2014.07.031

关键词

Podophyllotoxin; Benzimidazole; Cytotoxicity; Tubulin polymerization; Molecular docking

资金

  1. IICT-RMIT Research centre
  2. CSIR-New Delhi
  3. CSIR [CSC0301]

向作者/读者索取更多资源

A series of new podophyllotoxin derivatives containing structural modifications at C-7, C-8, and C-9 were synthesized and evaluated for their cytotoxic activity against three human cancer cell lines. All the synthesized compounds showed significant growth inhibition with GI(50) values in micromolar levels while some of the compounds were several times more potent against MCF-7 and HeLa cell lines than MIAPACA cell line. Three compounds (12a, 12d and 12e) emerged as potent compounds with broad spectrum of cytotoxic activity against all the tested cell lines with GI(50) values in the range of 0.01-2.1 mu M. These compounds induce microtubule depolymerization and arrests cells at the G2/M phase of the cell cycle. Moreover, compounds 12d and 12e disrupted microtubule network and accumulated tubulin in the soluble fraction in a similar manner to their parent podophyllotoxin scaffold. In addition, structure activity relationship studies within the series were also discussed. Molecular docking studies of these compounds into the colchicine-binding site of tubulin, revealed possible mode of inhibition by these compounds. (C) 2014 Elsevier Ltd. All rights reserved.

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