A novel aza-naphthoquinone inhibits tumor growth by inducing apoptosis  

一个新型氮杂萘醌类化合物通过诱导细胞凋亡来抑制肿瘤生长（英文）

作　　者：Li Lei Yu Chen Simin Yang Xiangbao Meng Siwang Yu 雷丽;陈宇;杨思敏;孟祥豹;余四旺(北京大学医学部药学院化学生物学系,北京100191)

机构地区：State Key Laboratory of Natural and Biomimetic Drugs,＂ Department of Molecular and Cellular Pharmacology,School of Pharmaceutical Sciences,Peking University Health Science Center,Beijing 100191,China

出　　处：《Journal of Chinese Pharmaceutical Sciences》2018年第9期600-607,共8页中国药学（英文版）

基　　金：National Natural Science Foundation of China(Grant No.81472657 and 81273370)

摘　　要：Natural product menaquinone has been reported to exhibit antitumor activity mediated by inhibiting IDO-1 enzyme, and naphthoquinone compounds like pyranaphthoquinone have attracted extensive research interests since they share the naphthoquinone pharmacophores. In the present study, a novel series of aza-naphthoquinones was synthesized based on 6,7-dichloroquinoline-5,8-dione structure, and their cytotoxicities were screened using lung cancer cells. Among them CY-26-11 was identified as the most potent one. CY-26-11 concentration-dependently induced apoptosis in A549 human lung adenocarcinoma cells, as indicated by annexin-V staining. Further experimental data show that CY-26-11 down-regulated Bcl-2 while up-regulated Bax and Puma protein levels, and activated caspase-3. Finally, CY-26-11 significantly inhibited the growth of Lewis lung carcinoma xenografts in vivo without significant major toxicities. Taken together, our results demonstrate that CY-26-11 exhibited IDO-l-independent anti-tumor effects both in vitro and in vivo, providing a new anti-tumor mechanism for naphthoquinone compounds.自发现天然产物甲萘醌具有通过抑制IDO-1酶介导的抗肿瘤活性以来,萘醌类化合物如吡喃萘醌引起了广泛的科研关注。在本研究中,我们基于6,7-二氯喹啉-5,8-二酮合成了一类新型的氮杂萘醌类化合物并进行了细胞毒筛选,发现其中CY-26-11的活性最佳。Annexin-V染色结果显示,CY-26-11浓度依赖地诱导A549人肺腺癌细胞凋亡。进一步的数据显示CY-26-11可下调抗凋亡蛋白Bcl-2,上调促凋亡蛋白Bax以及Puma,并激活caspase-3。最后, CY-26-11在小鼠路易斯肺癌皮下移植瘤模型中取得良好的抑瘤效果。总之,我们的实验结果说明CY-26-11具有良好的不依赖于IDO-1活性的体内外抗肿瘤作用,并为萘醌类化合物提供了抗肿瘤新机制。

关 键 词：NAPHTHOQUINONE CY-26-11 APOPTOSIS Anti-tumor activity 

分 类 号：R915[医药卫生—微生物与生化药学]