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.
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.
†Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.|‡Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
Hidemitsu
H
Minegishi
§Chemical Biology Research Group, RIKEN Center for Sustainable Resource Center, Hirosawa, Wako, Saitama 351-0198, Japan.
Yushi
Y
Futamura
‡Department of Life Science, Faculty of Science, Gakushuin University, Mejiro, Toshima-ku, Tokyo 171-8588, Japan.
Shinji
S
Fukashiro
§Chemical Biology Research Group, RIKEN Center for Sustainable Resource Center, Hirosawa, Wako, Saitama 351-0198, Japan.
Makoto
M
Muroi
§Chemical Biology Research Group, RIKEN Center for Sustainable Resource Center, Hirosawa, Wako, Saitama 351-0198, Japan.
Makoto
M
Kawatani
§Chemical Biology Research Group, RIKEN Center for Sustainable Resource Center, Hirosawa, Wako, Saitama 351-0198, Japan.
Hiroyuki
H
Osada
†Chemical Resources Laboratory, Tokyo Institute of Technology, Nagatsuta-cho, Midori-ku, Yokohama 226-8503, Japan.
Hiroyuki
H
Nakamura
D000890:Anti-Infective Agents / Q000737:chemistry / Q000494:pharmacology; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D060326:Chemistry Techniques, Synthetic; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D006367:HeLa Cells / Q000187:drug effects; D006801:Humans; D008826:Microbial Sensitivity Tests; D008870:Microtubules / Q000187:drug effects / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000737:chemistry / Q000494:pharmacology; D011720:Pyrazoles / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D050257:Tubulin Modulators / Q000737:chemistry / Q000494:pharmacology*; D062368:meta-Aminobenzoates / Q000737:chemistry / Q000494:pharmacology*
D000890:Anti-Infective Agents; D000962:Antimalarials; D000970:Antineoplastic Agents; C000600964:GN39482; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D050257:Tubulin Modulators; D062368:meta-Aminobenzoates