Sodwanone and yardenone triterpenes from a South African species of the marine sponge Axinella inhibit hypoxia-inducible factor-1 (HIF-1) activation in both breast and prostate tumor cells

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 anticancer 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 (IC50 15 mu M), and 8 was the only sodwanone that inhibited HIF-1 activation in PC- 3 prostate tumor cells ( IC50 15 AM). Compounds 1, 3, 4, and 5 inhibited hypoxia-induced HIF-1 activation in T47D cells (IC50 values 20-25 mu M). Compound 2 was cytotoxic to T47D cells ( IC50 22 AM), and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC50 23 mu M).