Methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate (GN39482) as a tubulin polymerization inhibitor identified by MorphoBase and ChemProteoBase profiling methods

J Med Chem. 2015 May 28;58(10):4230-41. doi: 10.1021/acs.jmedchem.5b00035. Epub 2015 May 11.

Abstract

A series of indenopyrazoles was synthesized from the corresponding indanones and phenyl isothiocyanates in two steps. Among the compounds synthesized, methyl 3-((6-methoxy-1,4-dihydroindeno[1,2-c]pyrazol-3-yl)amino)benzoate 6m (GN39482) was found to possess a promising antiproliferative activity toward human cancer cells without affecting any antimicrobial and antimalarial activities at 100 nM. Both a methoxy group at R(1) position and a methoxycarbonyl group at R(2) position of the anilinoquinazoline framework are essential for the high cell growth inhibition. Both MorphoBase and ChemProteoBase profiling analyses suggested that compound 6m was classified as a tubulin inhibitor. Indeed, compound 6m inhibited the acetylated tubulin accumulation and the microtubule formation and induced G2/M cell cycle arrest in HeLa cells, revealing that a promising antiproliferative activity of compound 6m toward human cancer cells is probably caused by the tubulin polymerization inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Infective Agents / chemistry
  • Anti-Infective Agents / pharmacology
  • Antimalarials / chemistry
  • Antimalarials / pharmacology
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology
  • Chemistry Techniques, Synthetic
  • Drug Evaluation, Preclinical / methods*
  • HeLa Cells / drug effects
  • Humans
  • Microbial Sensitivity Tests
  • Microtubules / drug effects
  • Microtubules / metabolism
  • Plasmodium falciparum / drug effects
  • Protein Kinase Inhibitors / chemistry
  • Protein Kinase Inhibitors / pharmacology
  • Pyrazoles / chemistry
  • Pyrazoles / pharmacology*
  • Structure-Activity Relationship*
  • Tubulin Modulators / chemistry
  • Tubulin Modulators / pharmacology*
  • meta-Aminobenzoates / chemistry
  • meta-Aminobenzoates / pharmacology*

Substances

  • Anti-Infective Agents
  • Antimalarials
  • Antineoplastic Agents
  • GN39482
  • Protein Kinase Inhibitors
  • Pyrazoles
  • Tubulin Modulators
  • meta-Aminobenzoates