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

摘要

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.