Novel derivatives of 1,3,4-oxadiazoles are potent mitostatic agents featuring strong microtubule depolymerizing activity in the sea urchin embryo and cell culture assays. Academic Article uri icon

start page

  • 1683

end page

  • 1697

abstract

  • A series of novel 1,3,4-oxadiazole derivatives based on structural and electronic overlap with combretastatins have been designed and synthesized. Initially, we tested all new compounds in vivo using the phenotypic sea urchin embryo assay to yield a number of agents with anti-proliferative, anti-mitotic, and microtubule destabilizing activities. The experimental data led to identification of 1,3,4-oxadiazole derivatives with isothiazole (5-8) and phenyl (9-12) pharmacophores featuring activity profiles comparable to that of combretastatins, podophyllotoxin and nocodazole. Cytotoxic effects of the two lead molecules, namely 6 and 12, were further confirmed and evaluated by conventional assays with the A549 human cancer cell line including cell proliferation, cell cycle arrest at the G2/M phase, cellular microtubule distribution, and finally in vitro microtubule assembly with purified tubulin. The modeling results using 3D similarity (ROCS) and docking (FRED) correlated well with the observed activity of the molecules. Docking data suggested that the most potent molecules are likely to target the colchicine binding site.Copyright (c) 2010 Elsevier Masson SAS. All rights reserved.

date/time value

  • 2010

Digital Object Identifier (DOI)

  • 10.1016/j.ejmech.2009.12.072

PubMed Identifier

  • 20110137

volume

  • 45

number

  • 5

keywords

  • Animals
  • Antineoplastic Agents
  • Biological Assay
  • Cell Cycle
  • Cell Proliferation
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Humans
  • Microtubules
  • Mitosis
  • Models, Molecular
  • Molecular Structure
  • Oxadiazoles
  • Phenotype
  • Sea Urchins
  • Structure-Activity Relationship
  • Tumor Cells, Cultured