Synthesis and biological evaluation of 1,2,3-triazole linked aminocombretastatin conjugates as mitochondrial mediated apoptosis inducers

Bioorg Med Chem. 2014 Oct 1;22(19):5155-67. doi: 10.1016/j.bmc.2014.08.008. Epub 2014 Aug 19.


A series of 1,2,3-triazole linked aminocombretastatin conjugates were synthesized and evaluated for cytotoxicity, inhibition of tubulin polymerization and apoptosis inducing ability. Most of the conjugates exhibited significant anticancer activity against some representative human cancer cell lines and two of the conjugates 6d and 7c displayed potent cytotoxicity with IC50 values of 53 nM and 44 nM against A549 human lung cancer respectively, and were comparable to combretastatin A-4 (CA-4). SAR studies revealed that 1-benzyl substituted triazole moiety with an amide linkage at 3-position of B-ring of the combretastatin subunit are more active compared to 2-position. G2/M cell cycle arrest was induced by these conjugates 6d and 7c and the tubulin polymerization assay (IC50 of 1.16 μM and 0.95 μM for 6d and 7c, respectively) as well as immunofluorescence analysis showed that these conjugates effectively inhibit microtubule assembly at both molecular and cellular levels in A549 cells. Colchicine competitive binding assay suggested that these conjugates bind at the colchicine binding site of tubulin as also observed from the docking studies. Further, mitochondrial membrane potential, ROS generation, caspase-3 activation assay, Hoechst staining and DNA fragmentation analysis revealed that these conjugates induce cell death by apoptosis.

Keywords: CA-4; Cell cycle; Cytotoxicity; Triazoles; Tubulin polymerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Bibenzyls / chemistry
  • Bibenzyls / pharmacology*
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • HeLa Cells
  • Hep G2 Cells
  • Humans
  • MCF-7 Cells
  • Mitochondria / metabolism*
  • Molecular Structure
  • Structure-Activity Relationship
  • Triazoles / chemical synthesis
  • Triazoles / chemistry
  • Triazoles / pharmacology*
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*


  • Antineoplastic Agents
  • Bibenzyls
  • Triazoles
  • Tubulin Modulators
  • combretastatin