Synthesis and biological evaluation of novel 3,4-diaryl-1,2,5-selenadiazol analogues of combretastatin A-4

Eur J Med Chem. 2014 Nov 24:87:1-9. doi: 10.1016/j.ejmech.2014.09.046. Epub 2014 Sep 16.

Abstract

A set of novel selenium-containing heterocyclic analogues of combretastatin A-4 (CA-4) have been designed and synthesised using a rigid 1,2,5-selenadiazole as a linker to fix the cis-orientation of ring-A and ring-B. All of the target compounds were evaluated for their in vitro anti-proliferative activities. Among these compounds, compounds 3a, 3i, 3n and 3q exhibited superior potency against different tumour cell lines with IC50 values at the nanomolar level. Moreover, compound 3n significantly induced cell cycle arrest in the G2/M phase, inhibited tubulin polymerisation into microtubules and caused microtubule destabilisation. A molecular modelling study of compound 3n was performed to elucidate its binding mode at the colchicine site in the tubulin dimer and to provide a basis for the further structure-guided design of novel CA-4 analogues.

Keywords: 3,4-Diaryl-1,2,5-selenadiazol; Anti-proliferative activity; Combretastatin A-4; Molecular modelling; Synthesis; Tubulin.

Publication types

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

MeSH terms

  • Antineoplastic Agents, Phytogenic / chemical synthesis*
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Bibenzyls / chemistry*
  • Cell Cycle / drug effects
  • Cell Proliferation / drug effects*
  • Drug Screening Assays, Antitumor
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Heterocyclic Compounds / chemistry
  • Humans
  • Models, Molecular
  • Molecular Structure
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Selenium / chemistry*
  • Stilbenes / chemical synthesis*
  • Stilbenes / pharmacology*
  • Structure-Activity Relationship
  • Tumor Cells, Cultured

Substances

  • Antineoplastic Agents, Phytogenic
  • Bibenzyls
  • Heterocyclic Compounds
  • Stilbenes
  • combretastatin
  • Selenium
  • fosbretabulin