title: Inducers of hypoxic response: marine sesquiterpene quinones activate HIF-1.
abstract: The hypoxia-inducible factor-1 (HIF-1) transcription factor regulates cellular oxygen homeostasis. Agents that activate HIF-1 and downstream HIF targets represent potential drug leads for the prevention and/or treatment of ischemic disorders. In a search for small-molecule HIF-1 activators, 1936 marine invertebrate and algal extract samples (U.S. National Cancer Institute's Open Repository) were evaluated for HIF-1 activation activity in a cell-based reporter assay. Bioassay-guided fractionation of two active extracts of the sponge Dactylospongia elegans afforded four new sesquiterpene quinones (2-5), one new sesquiterpene phenol (6), the known Golgi disruptor ilimaquinone (1), and three previously reported ilimaquinone analogues (7-9). While antiproliferative activity was observed at higher concentrations, the sesquiterpene quinones (1-3) possessing a 2-hydroxy-5-methoxy-1,4-benzoquinone moiety activated HIF-1 and increased the expression of HIF-1 target gene vascular endothelial growth factor (VEGF) in T47D cells.
authors.affiliation: Department of Pharmacognosy, School of Pharmacy, University of Mississippi, University, Mississippi 38677, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Du
authors.forename: Yu-Dong
authors.initials: YD
authors.lastname: Zhou
authors.forename: Dale G
authors.initials: DG
authors.lastname: Nagle
mesh_terms: D000818:Animals; D004305:Dose-Response Relationship, Drug; D005260:Female; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000187:drug effects*; D015394:Molecular Structure; D019906:Nuclear Magnetic Resonance, Biomolecular; D009792:Oceans and Seas; D011161:Porifera / Q000737:chemistry*; D011809:Quinones / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D012717:Sesquiterpenes / Q000737:chemistry / Q000302:isolation & purification* / Q000494:pharmacology*; D042461:Vascular Endothelial Growth Factor A / Q000187:drug effects
chemical_list: D051793:Hypoxia-Inducible Factor 1; D011809:Quinones; D012717:Sesquiterpenes; D042461:Vascular Endothelial Growth Factor A