Design and synthesis of new 2-arylnaphthyridin-4-ones as potent antitumor agents targeting tumorigenic cell lines

Chin Yu Liu, Yung Yi Cheng, Ling Chu Chang, Li Jiau Huang, Li Chen Chou, Chi Hung Huang, Meng Tung Tsai, Chih Chang Liao, Mei Hua Hsu, Hui Yi Lin, Tian Shung Wu, Yen Fang Wen, Yu Zhao, Sheng Chu Kuo, Kuo Hsiung Lee

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3g?2-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3g?2-methoxy moiety on the C-ring phenyl group of AN (6a-e) with 3g?2-hydroxy (7a-e) made no significant effect on the inhibitory activity against HL-60, Hep3B and NCI-H460 cancer cell lines. On the other hand, replacing the 6-methoxy group on the A-ring of AN (6g-i) with a 6-hydroxy group (7g-i) resulted in reduced inhibitory activity against the above three cancer cell lines. Among the above-mentioned target compounds, 2-(3-hydroxyphenyl)-5-methyl-1,8-naphthyridin-4(1H)-one (7a) demonstrated the greatest potency and the best selectivity toward tumorigenic cancer cell lines. In a 7a preliminary mechanism of action study in Hep3B hepatoma cells, 7a showed the effects on microtubules followed by cell cycle arrest and sequentially led to apoptosis.In addition, a phosphate prodrug (11) of 7a exhibited significant antitumor activity when tested in a Hep3B xenograft nude mice model. Since compound 11 has demonstrated good development potential, it is recommended for further preclinical studies.

Original languageEnglish
Pages (from-to)775-787
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume90
DOIs
Publication statusPublished - 2015 Jan 27

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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