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.

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.

• Authors: Hidemitsu Minegishi, Yushi Futamura, Shinji Fukashiro, Makoto Muroi, Makoto Kawatani, Hiroyuki Osada, Hiroyuki Nakamura
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 58 Issue 10 Pg. 4230-41 (May 28 2015) ISSN: 1520-4804 [Electronic] United States
• PMID: 25938266 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

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

Topics

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