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.

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