Design, synthesis and biological evaluation of colchicine derivatives as novel tubulin and histone deacetylase dual inhibitors

Eur J Med Chem. 2015 May 5:95:127-35. doi: 10.1016/j.ejmech.2015.03.035.

Xuan Zhang ¹, Yannan Kong ², Jie Zhang ³, Mingbo Su ⁴, Yubo Zhou ⁴, Yi Zang ⁴, Jia Li ⁴, Yi Chen ³, Yanfen Fang ⁵, Xiongwen Zhang ², Wei Lu ⁶

Affiliations

1 Institute of Drug Discovery and Development, East China Normal University, Shanghai 200062, PR China.
2 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, PR China.
3 State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
4 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, PR China.
5 Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, East China Normal University, Shanghai 200062, PR China. Electronic address: yffang@sat.ecnu.edu.cn.
6 Institute of Drug Discovery and Development, East China Normal University, Shanghai 200062, PR China. Electronic address: wlu@chem.ecnu.edu.cn.

PMID: 25805446 DOI: 10.1016/j.ejmech.2015.03.035

Abstract

A new class of colchicine derivatives were designed and synthesized as tubulin-HDAC dual inhibitors. Biological evaluations of these hybrids included the inhibitory activity of HDAC, tubulin polymerization analysis, in vitro cell cycle analysis in HCT-116 cells and cytotoxicity against different Cancer cell lines. Hybrid 6d behaved as potent HDAC-tubulin dual inhibitor and showed comparable cytotoxicity with colchicine. Compound 11a exhibited powerful tubulin inhibitory activity, moderate anti-HDAC activity and the most potent cytotoxicity (IC50 = 2-105 nM).

Keywords

Colchicine; Dual inhibitor; HDAC; Hybrid; Tubulin.

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