Synthesis and c-met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines

Identification of 3-(4-acetylpiperazin-1-yl)-5- (3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent

Yuanxiang Wang, Jing Ai, Ying Wang, Yi Chen, Lu Wang, Gang Liu, Meiyu Geng, Ao Zhang

Research output: Contribution to journalArticle

66 Citations (Scopus)

Abstract

By use of an improved synthetic strategy, a series of 3,5-disubstituted and 3,5,7-trisubstituted quinolines were readily prepared. 3,5,7-Trisubstituted quinolines 21a-c, 21l, and 27a-c were identified as the most potent c-Met inhibitors with IC50 of less than 1.0 nM. Compound 21b showed the most promising overall PK profile and has high potency and extraordinary selectivity to c-Met against c-Met family member Ron and 12 other tyrosine kinases. It produced constitutive inhibition of c-Met phosphorylation in c-Met dependent cell lines. At doses of 100 mg/kg, compound 21b showed statistically significant tumor growth inhibition (68-69%) in both NIH-3T3-TPR-Met and U-87 MG human gliobastoma xenograft models. These results clearly indicated that compound 21b is a potent and highly selective c-Met inhibitor. Its favorable in vitro and in vivo profiles warrant further investigation.

Original languageEnglish (US)
Pages (from-to)2127-2142
Number of pages16
JournalJournal of Medicinal Chemistry
Volume54
Issue number7
DOIs
StatePublished - Apr 14 2011
Externally publishedYes

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Quinolines
Antineoplastic Agents
Phosphotransferases
Heterografts
Protein-Tyrosine Kinases
Inhibitory Concentration 50
Phosphorylation
Cell Line
Growth
Neoplasms
Inhibition (Psychology)
quinoline
In Vitro Techniques

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

Cite this

Synthesis and c-met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines : Identification of 3-(4-acetylpiperazin-1-yl)-5- (3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent. / Wang, Yuanxiang; Ai, Jing; Wang, Ying; Chen, Yi; Wang, Lu; Liu, Gang; Geng, Meiyu; Zhang, Ao.

In: Journal of Medicinal Chemistry, Vol. 54, No. 7, 14.04.2011, p. 2127-2142.

Research output: Contribution to journalArticle

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