Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors

Hypoxia-inducible factor-1 (HIF-1) is the chief transcription factor regulating hypoxia-driven gene expression. HIF-1 overexpression is associated with poor prognosis in several cancers and therefore represents an attractive target for novel antitumor agents. We explored small molecule inhibitors of the HIF-1 pathway. Using high-throughput-screening, we identified benzanilide compound 1 (IC50 = 560 nM) as a seed. Subsequent extensive derivatization led to the discovery of compounds 43a and 51d, with anti-HIF-1 activities in vitro (IC50 = 21 and 0.47 nM, respectively), and in vivo. Additionally, 43a (12.5-100 mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.