Synthesis of triazoloquinazolinone based compounds as tubulin polymerization inhibitors and vascular disrupting agents

Eur J Med Chem. 2016 Jun 10:115:393-405. doi: 10.1016/j.ejmech.2016.03.056. Epub 2016 Mar 22.

Abstract

A series of 1-phenyl-[1,2,4]triazolo[4,3-a]quinazolin-5-ones designed as conformationally restricted CA-4 analogues, were tested for their tubulin polymerization and growth inhibitory activities. The 3-hydroxy-4-methoxy derivatives 11d and 12d are potent inhibitors of tubulin assembly but only the N-methylated amid counterpart 12d possesses potent anticancer activity in a large panel of cancer cell lines. Upon treatment with compound 12d, remarkable cell shape changes as cell migration and tube formation were elicited in HUVECs, consistent with vasculature damaging activity.

Keywords: Antivascular; Combretastatin; Cytotoxicity; Triazoloquinazolinone; Tubulin polymerization.

MeSH terms

  • Blood Vessels / drug effects*
  • Cell Proliferation / drug effects
  • Polymerization
  • Quinazolinones / pharmacology*
  • Tubulin / chemistry*
  • Tubulin Modulators / pharmacology*

Substances

  • Quinazolinones
  • Tubulin
  • Tubulin Modulators