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

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

来源：European Journal of Medicinal Chemistry, 2015, 90: 775-787.

DOI：10.1016/j.ejmech.2014.11.062

• 2-Arylnaphthyridin-4-ones
• Antitumor agents
• Phosphate prodrug

To develop new anticancer drug candidates from 2-arylnaphthyridin-4-one (AN), we have designed and synthesized a series of 3'-hydroxy and 6-hydroxy derivatives of AN. The results of cytotoxicity screening indicated that the replacement of the 3'-methoxy moiety on the C-ring phenyl group of AN (6a-e) with 3'-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.

• 出版日期2015-1-27
• 单位中国医科大学; 中国科学院昆明植物研究所