Bian Jinlei, Deng Bang, Xu Lili, Xu Xiaoli, Wang Nan, Hu Tianhan, Yao Zeyu, Du Jianyao, Yang Li, Lei Yonghua, Li Xiang, Sun Haopeng, Zhang Xiaojin, You Qidong
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 210009, China; Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Department of Medicinal Chemistry, School of Pharmacy, China Pharmaceutical University, Nanjing 210009, China.
Eur J Med Chem. 2014 Jul 23;82:56-67. doi: 10.1016/j.ejmech.2014.05.041. Epub 2014 May 14.
A series of L-shaped ortho-quinone analogs were designed by analyzing the binding mode with NQO1. Metabolic studies demonstrated that compounds 2m, 2n and 2q exhibited higher metabolic rates than β-lapachone. The docking studies, which supported the rationalization of the metabolic studies, constituted a prospective rational basis for the development of optimized ortho-quinone analogs. Besides, good substrates (2m, 2n and 2r) for NQO1 showed higher selective toxicity than β-lapachone toward A549 (NQO1-rich) cancer cells versus H596 (NQO1-deficient) cells. Determination of superoxide (O2(•-)) production and in vitro cytotoxicity evaluation in the presence of the NQO1 inhibitor dicoumarol confirmed that the ortho-quinones exerted their antitumor activity through NQO1-mediated ROS production by redox cycling. It was suggested that the L-shaped quinone substrates for NQO1 possessed better specificity and safety than β-lapachone.
通过分析与NQO1的结合模式，设计了一系列L形邻醌类似物。代谢研究表明，化合物2m、2n和2q的代谢率高于β-拉帕醌。对接研究支持了代谢研究的合理性，为优化邻醌类似物的开发提供了前瞻性的合理依据。此外，NQO1的良好底物（2m、2n和2r）对富含NQO1的A549癌细胞与缺乏NQO1的H596细胞显示出比β-拉帕醌更高的选择性毒性。在NQO1抑制剂双香豆素存在下测定超氧化物（O2(•-)）生成并进行体外细胞毒性评估，证实邻醌通过氧化还原循环由NQO1介导的ROS生成发挥其抗肿瘤活性。有人认为，NQO1的L形醌底物比β-拉帕醌具有更好的特异性和安全性。
