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
Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan.
Graduate Institute of Pharmaceutical Chemistry, China Medical University, No. 91 Hsueh-Shih Road, Taichung 40402, Taiwan; Graduate School of Biotechnology, Hung Kuang University, No. 1018, Sec. 6 Taiwan Boulevard, Shalu District, Taichung 43302, Taiwan.
Eur J Med Chem. 2015 Jan 27;90:775-87. doi: 10.1016/j.ejmech.2014.11.062. Epub 2014 Dec 11.
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.
为了从2-芳基萘啶-4-酮（AN）开发新的抗癌候选药物，我们设计并合成了一系列AN的3'-羟基和6-羟基衍生物。细胞毒性筛选结果表明，将AN（6a-e）的C环苯基上的3'-甲氧基部分替换为3'-羟基（7a-e）对HL-60、Hep3B和NCI-H460癌细胞系的抑制活性没有显著影响。另一方面，将AN（6g-i）的A环上的6-甲氧基替换为6-羟基（7g-i）导致对上述三种癌细胞系的抑制活性降低。在上述目标化合物中，2-(3-羟基苯基)-5-甲基-1,8-萘啶-4(1H)-酮（7a）对致瘤癌细胞系表现出最大的效力和最佳的选择性。在对Hep3B肝癌细胞进行的7a初步作用机制研究中，7a显示出对微管的影响，随后导致细胞周期停滞并依次导致细胞凋亡。此外，7a的磷酸前药（11）在Hep3B异种移植裸鼠模型中测试时表现出显著的抗肿瘤活性。由于化合物11已显示出良好的开发潜力，建议进行进一步的临床前研究。
