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

Xuan Zhang; Yannan Kong; Jie Zhang; Mingbo Su; Yubo Zhou; Yi Zang; Jia Li; Yi Chen; Yanfen Fang; Xiongwen Zhang; Wei Lu

doi:10.1016/j.ejmech.2015.03.035

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. Epub 2015 Mar 18.

Authors

Xuan Zhang¹, Yannan Kong², Jie Zhang³, Mingbo Su⁴, Yubo Zhou⁴, Yi Zang⁴, Jia Li⁴, Yi Chen³, Yanfen Fang⁵, Xiongwen Zhang², Wei Lu⁶

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.

Publication types

Evaluation Study
Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents / chemical synthesis
Antineoplastic Agents / pharmacology
Cell Cycle / drug effects
Cell Proliferation / drug effects
Colchicine / chemistry*
Colchicine / pharmacology*
Drug Design*
Drug Screening Assays, Antitumor
HCT116 Cells
Histone Deacetylase Inhibitors / chemical synthesis*
Histone Deacetylase Inhibitors / pharmacology*
Histone Deacetylases / chemistry
Humans
Structure-Activity Relationship
Tubulin / chemistry
Tubulin Modulators / chemical synthesis*
Tubulin Modulators / pharmacology*

Substances

Antineoplastic Agents
Histone Deacetylase Inhibitors
Tubulin
Tubulin Modulators
Histone Deacetylases
Colchicine