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.
Mohsine Driowya  1 ,  Julien Leclercq  1 ,  Valerie Verones  1 ,  Amélie Barczyk  2 ,  Marie Lecoeur  3 ,  Nicolas Renault  2 ,  Nathalie Flouquet  1 ,  Alina Ghinet  4 ,  Pascal Berthelot  1 ,  Nicolas Lebegue  5
Affiliations
  • 1. Université de Lille, F-59000 Lille, France; Inserm UMR-S1172, Onco and NeuroChemistry, Jean-Pierre Aubert Research Center, F-59000 Lille, France.
  • 2. Université de Lille, F-59000 Lille, France; Inserm UMR-995, Institut de Chimie Pharmaceutique Albert Lespagnol, F-59000 Lille, France.
  • 3. Université de Lille, F-59000 Lille, France; UDSL, EA 7365 GRITA, 59000 Lille Cedex, France.
  • 4. Université de Lille, F-59000 Lille, France; Inserm UMR-995, Hautes Etudes Ingénieur, F-59000 Lille, France.
  • 5. Université de Lille, F-59000 Lille, France; Inserm UMR-S1172, Onco and NeuroChemistry, Jean-Pierre Aubert Research Center, F-59000 Lille, France. Electronic address: [email protected].
PMID: 27031215 DOI: 10.1016/j.ejmech.2016.03.056
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.