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

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• 作者：Jingqiu Dai ; James A. Fishback ; Yu-Dong Zhou ; Dale G. Nagle
• 刊名：Journal of Natural Products
• 出版年：2006
• 出版时间：December 2006
• 年：2006
• 卷：69
• 期：12
• 页码：1715 - 1720
• 全文大小：103K
• 年卷期：v.69,no.12(December 2006)
• ISSN：1520-6025

文摘

Hypoxia-inducible factor-1 (HIF-1) is a transcription factor that promotes tumor cell adaptation and survival underhypoxic conditions. HIF-1 is currently recognized as an important molecular target for anticancer drug discovery. AT47D breast tumor cell-based reporter assay was used to evaluate the NCI Open Repository of marine invertebrates andalgae lipid extracts for HIF-1 inhibitory activity. Bioassay-guided fractionation and isolation of an active extract fromAxinella 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 structuresand relative configurations of these Axinella metabolites were determined spectroscopically. The absolute configurationof 1 was determined by the modified Mosher ester procedure. Sodwanone V (8) inhibited both hypoxia-induced andiron chelator (1,10-phenanthroline)-induced HIF-1 activation in T47D breast tumor cells (IC₅₀ 15 M), and 8 was theonly sodwanone that inhibited HIF-1 activation in PC-3 prostate tumor cells (IC₅₀ 15 M). Compounds 1, 3, 4, and 5inhibited hypoxia-induced HIF-1 activation in T47D cells (IC₅₀ values 20-25 M). Compound 2 was cytotoxic toT47D cells (IC₅₀ 22 M), and 8 showed cytotoxicity to MDA-MB-231 breast tumor cells (IC₅₀ 23 M).