[1,2]Oxazolo[5,4-e]isoindoles as promising tubulin polymerization inhibitors

Eur J Med Chem. 2016 Nov 29:124:840-851. doi: 10.1016/j.ejmech.2016.09.013. Epub 2016 Sep 5.

Abstract

A series of [1,2]Oxazolo [5,4-e]isoindoles has been synthesized through a versatile and high yielding sequence. All the new structures showed in the 1HNMR spectra, the typical signal in the 8.34-8.47 ppm attributable to the H-3 of the [1,2]oxazole moiety. Among all derivatives, methoxy benzyl substituents at positions 3 and 4 or/and 5 were very effective in reducing the growth of different tumor cell lines, including diffuse malignant peritoneal mesothelioma (DMPM), an uncommon and rapidly malignancy poorly responsive to available therapeutic options. The most active compound 6j was found to impair tubulin polymerization, cause cell cycle arrest at G2/M phase and induce apoptosis in DMPM cells, making it as a new lead for the discovery of new potent antimitotic drugs.

Keywords: Antitubulin agents; Diffuse malignant peritoneal mesothelioma; [1,2]Oxazolo[5,4-e]isoindoles; α-hydroxyalkyl ketones.

MeSH terms

  • Antineoplastic Agents / chemical synthesis
  • Antineoplastic Agents / chemistry*
  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Drug Screening Assays, Antitumor
  • G2 Phase Cell Cycle Checkpoints / drug effects
  • Humans
  • Isoindoles / chemical synthesis
  • Isoindoles / chemistry*
  • Isoindoles / pharmacology*
  • Isomerism
  • M Phase Cell Cycle Checkpoints / drug effects
  • Protein Multimerization / drug effects*
  • Protein Structure, Quaternary
  • Tubulin / chemistry
  • Tubulin Modulators / chemical synthesis
  • Tubulin Modulators / chemistry*
  • Tubulin Modulators / pharmacology*

Substances

  • Antineoplastic Agents
  • Isoindoles
  • Tubulin
  • Tubulin Modulators