Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival under hypoxic conditions. HIF-1 is currently recognized as an important molecular target for anti-cancer drug discovery. A T47D breast tumor cell-based reporter assay was used to evaluate the NCI Open Repository of marine invertebrates and algae lipid extracts for HIF-1 inhibitory activity. Bioassay-guided fractionation and isolation of an active extract from Axinella sp. yielded seven new sodwanone triterpenoids [3-epi-sodwanone K (1), 3-epi-sodwanone K 3-acetate (2), 10,11-dihydrosodwanone B (4), sodwanones T-W (3, 7, 8, 9), the new yardenone triterpene 12R-hydroxyyardenone (10), and the previously reported compounds sodwanone A (5), sodwanone B (6), and yardenone (11). The structures and relative configurations of these Axinella metabolites were determined spectroscopically. The absolute configuration of 1 was determined by the modified Mosher ester procedure. Sodwanone V (8) inhibited both hypoxia-induced and iron chelator (1,10-phenanthroline)-induced HIF-1 activation in T47D breast tumor cells (IC 50 15 μM) and 8 was the only sodwanone that inhibited HIF-1 activation in PC-3 prostate tumor cells (IC 50 15 μM). Compounds 1, 3, 4, and 5 inhibited hypoxia-induced HIF-1 activation in T47D cells . Compound 2 was cytotoxic to T47D cells (IC 50 22 μM) and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC 50 23 μM).Intratumoral hypoxia (a reduced state of oxygen tension) is a common feature of solid tumors. 1,2 The extent of tumor hypoxia correlates with advanced disease stages, malignant progression, poor prognosis, and is a significant contributor to radiation and chemotherapy treatment resistance. 1-3 Current approaches to overcome tumor hypoxia include those that increase oxygenation during radiotherapy and those that develop hypoxia-activated prodrugs such as radiation sensitizers and hypoxia-activated cytotoxins. [1][2][3] No small molecule drug that specifically targets tumor hypoxia is in clinical use and there are only two hypoxic cytotoxins (tirapazamine and AQ4N) in clinical trials. 1 The promising results from tirapazamine clinical trials (phase II and III) have validated the feasibility of small molecule drugs that target tumor hypoxia. 4 However, the application of tirapazamine for cancer treatment is limited by toxicity.* Joint Corresponding Authors to whom correspondence should be addressed: Yu-Dong Zhou: Tel. (662) To discover potential drug leads that target tumor hypoxia, our research efforts focus on the discovery of natural product-derived inhibitors of hypoxia-inducible factor-1 (HIF-1). First identified as a transcription factor that is activated by hypoxia, 5 HIF-1 has been shown to be a major regulator of oxygen homeostasis. 2,[6][7][8] Extensive studies indicate that HIF-1 plays an important role in cancer biology by regulating the expression of hundreds of genes. 2,[6][7][8] The processes that are regulated by HIF-1 target genes range from tumorigenesis, angioge...