3-substituted 2-phenylimidazo[2,1-b]benzothiazoles: synthesis, anticancer activity, and inhibition of tubulin polymerization

ChemMedChem. 2012 Feb 6;7(2):292-300. doi: 10.1002/cmdc.201100511. Epub 2012 Jan 12.

Abstract

A new series of 3-substituted 2-phenylimidazo[2,1-b]benzothiazoles (3 a-h) were synthesized by C-arylation of 2-arylimidazo[2,1-b]benzothiazoles using palladium acetate as catalyst, and the resulting compounds were evaluated for their anticancer activity. Compounds 3 a, 3 e, and 3 h exhibited good antiproliferative activity, with GI50 values in the range of 0.19-83.1 μM. Compound 3 h showed potent anticancer efficacy against 60 human cancer cell lines, with a mean GI50 value of 0.88 μM. This compound also induced cell-cycle arrest in the G2/M phase and inhibited tubulin polymerization followed by activation of caspase-3 and apoptosis. A high-throughput tubulin polymerization assay showed that the level of inhibition for compound 3 h is similar to that of combretastatin A-4. Molecular modeling studies provided a molecular basis for the favorable binding of compounds 3 a, 3 e, and 3 h to the colchicine binding pocket of tubulin.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / chemical synthesis*
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / therapeutic use
  • Benzothiazoles / chemistry*
  • Benzothiazoles / pharmacology
  • Benzothiazoles / therapeutic use
  • Binding Sites
  • Cell Cycle Checkpoints
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Colchicine / chemistry
  • Computer Simulation
  • Drug Screening Assays, Antitumor
  • Humans
  • Imidazoles / chemistry*
  • Neoplasms / drug therapy
  • Polymerization / drug effects
  • Protein Structure, Tertiary
  • Structure-Activity Relationship
  • Tubulin / chemistry*
  • Tubulin / metabolism
  • Tubulin Modulators / chemical synthesis*
  • Tubulin Modulators / therapeutic use

Substances

  • Antineoplastic Agents
  • Benzothiazoles
  • Imidazoles
  • Tubulin
  • Tubulin Modulators
  • imidazole
  • Colchicine