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.
1.China Med Univ, Grad Inst Pharmaceut Chem, Taichung 40402, Taiwan 2.Hung Kuang Univ, Grad Sch Biotechnol, Taichung 43302, Taiwan 3.Natl Cheng Kung Univ, Dept Chem, Tainan 70101, Taiwan 4.Ind Technol Res Inst, Hsinchu 31040, Taiwan 5.Chinese Acad Sci, Kunming Inst Bot, Kunming 650201, Yunnan, Peoples R China 6.Univ N Carolina, UNC Eshelman Sch Pharm, Nat Prod Res Labs, Chapel Hill, NC 27599 USA 7.China Med Univ & Hosp, Chinese Med Res & Dev Ctr, Taichung 40447, Taiwan