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: [email protected].
  • 6. Institute of Drug Discovery and Development, East China Normal University, Shanghai 200062, PR China. Electronic address: [email protected].
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.