Hypoxia-inducible factor 1 (HIF-1) is heterodimer consisting of a constitutively expressed HIF-1� and an O2-regulated HIF-1a as subunits. Under aerobic conditions, HIF-1a is polyubiquitinated and then degraded by proteasomes, leading to HIF-1 suppression. However, HIF-1a under hypoxia is not degraded and intact HIF-1a dimerizes with HIF-1� leading to activation of HIF-1, which play key roles in physiological processes of cell survival and cancer development.YC-1, 3-(5'-hydroxymethyl-2'-furyl)-1-benzyl indazole, has been considered as one of the most attractive drug candidates due to its potent inhibitory activity against HIF-1a and a novel privileged indazole structure, which was found in a variety of chemotherapeutics with diverse pharmacological effects. Herein, we report design, synthesis and insight into the structure-activity relationship of the 1, 3-disubstituted indazoles based on YC-1 as novel HIF-1a inhibitors. In particular, the substituted furan moiety on indazole skeleton as well as its substitution pattern turns out crucial for the high HIF-1a inhibition.

Design, synthesis and insight into the structure-activity relationship of 1,3-disubstituted indazoles as novel HIF-1 inhibitors

243rd National Meeting (2012)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.