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

Eighteen new beta-carboline-based indole-4,7-quinone derivatives (12a-iand13a-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 compound13gnot only displayed more prominent antiproliferative activities than beta-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,13gdose-dependently induced high ROS levels in HT29 cells, and selectively inhibited cancer cell but not non-tumor colon cell proliferation in vitro. Importantly,13gpromoted HT29 cell apoptosis and DNA damage by regulating relative apoptotic proteins and H2AX expression. Finally,13gdisplayed significant growth inhibition of HT29 human colorectal adenocarcinoma xenograft in mice without overt toxicity.