Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors.
Basic Information
ID: ALA3351307
Journal: Bioorg Med Chem
Title: Synthesis and structure-activity relationships of novel, potent, orally active hypoxia-inducible factor-1 inhibitors.
Authors: Nagao S, Yamane Y, Funasaka S, Tanaka K, Miyazaki K, Kotake Y, Kamata J, Watanabe-Miyano S, Toyama O, Ozawa Y, Mizui Y, Okamoto K, Ito D.
Abstract: 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 (12.5-100mg/kg) also displayed in vivo anti-tumor efficacy, without influencing body weight.
CiteXplore: 25139751
DOI: 10.1016/j.bmc.2014.07.020
Patent ID: ┄