Novel β‐carboline‐based indole‐4,7‐quinone derivatives as NAD(P)H: Quinone‐oxidoreductase‐1 inhibitor with potent antitumor activities by inducing reactive oxygen species, apoptosis, and DNA damage

• Published in: Chemical biology & drug design 2020-12, Vol.96 (6), p.1433-1446
• Main Authors: Guo, Yibing, Xu, Liancheng, Ling, Changchun, Yang, Tao, Zheng, Wenjie, Lv, Jin, Guo, Qingsong, Chen, Bohua
• Format: Article
• Language: English
• Subjects: antitumor activity; apoptosis; indole‐4,7‐quinone derivatives; quinone oxidoreductase 1; reactive oxygen species; β‐Carboline
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13752

Eighteen new β‐carboline‐based indole‐4,7‐quinone derivatives (12a–i and 13a–i) were designed and synthesized, and their in vitro and in vivo antiproliferative activities were studied. Most of target compounds showed strong inhibition on three human tumor cells' proliferation. In particular, the most active compound 13g not only displayed more prominent antiproliferative activities than β‐lapachone, a clinical antitumor candidate, but also exerted significant NAD(P)H: quinone‐oxidoreductase‐1 (NQO1) inhibitory activity and NQO1‐dependent cytotoxicity in HT29 cells. Furthermore, 13g dose‐dependently induced high ROS levels in HT29 cells, and selectively inhibited cancer cell but not non‐tumor colon cell proliferation in vitro. Importantly, 13g promoted HT29 cell apoptosis and DNA damage by regulating relative apoptotic proteins and H2AX expression. Finally, 13g displayed significant growth inhibition of HT29 human colorectal adenocarcinoma xenograft in mice without overt toxicity. The most potent β‐carboline‐based indole‐4,7‐quinone derivative 13g not only exhibited more potent antitumor activity than β‐lapachone in vitro and in vivo, but also exerted significant NQO1 inhibitory effect, and dose‐dependently induced high ROS level, apoptosis, and DNA damage in colonic cancer cells.