Inducers of Hypoxic Response: Marine Sesquiterpene Quinones Activate HIF‑1

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 <i>Dactylospongia elegans</i> afforded four new sesquiterpene quinones (<b>2</b>–<b>5</b>), one new sesquiterpene phenol (<b>6</b>), the known Golgi disruptor ilimaquinone (<b>1</b>), and three previously reported ilimaquinone analogues (<b>7</b>–<b>9</b>). While antiproliferative activity was observed at higher concentrations, the sesquiterpene quinones (<b>1</b>–<b>3</b>) 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