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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
Author(s) -
Guo Yibing,
Xu Liancheng,
Ling Changchun,
Yang Tao,
Zheng Wenjie,
Lv Jin,
Guo Qingsong,
Chen Bohua
Publication year - 2020
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/cbdd.13752
Subject(s) - nad+ kinase , apoptosis , quinone , cell growth , cytotoxicity , in vitro , dna damage , chemistry , reactive oxygen species , in vivo , biochemistry , oxidoreductase , cell culture , biology , microbiology and biotechnology , dna , enzyme , genetics
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.