Synthesis of Analogues of (+)-Gomphoside, a Potent HIF-1 Inhibitor and Cardenolide

Abstract

The milkweed bush Gomphocarpus fruticosus R.Br. found in Australia contains the steroidal glycoside (+)-gomphoside, its derivatives (-)-3'-dehydrogomphoside and (+)-3'- epi-gomphoside, as well as other glycoside compounds. The key structural features of these unique herbal agents are bislinked steroid to sugar linkages. (+)-Gomphoside is an extremely potent cardenolide and highly effective Hypoxia-Inducible Factor (HIF)-1 inhibitor. In addition, (+)-gomphoside exhibits strong cytotoxicity on human breast cancer cell lines. The syntheses of (+)-gomphoside analogues with modified steroidal D rings are described here. The syntheses started with glycosylation of (+)-(2α,3β,5α)-2,3-cholestanediol with benzoylated 2-keto sugar bromides, promoted by silver carbonate. Two regioisomeric glycosides with bent up and bent down ring anellation geometry were obtained, because of the two hydroxyl groups in the diol. Modification of the sugar ring of these glycosides by base-induced elimination of benzoic acid yielded (-)-3'-dehydrogomphoside analogues. The analogues of (+)-gomphoside and (+)-3'- epi-gomphoside were then obtained by stereoselective reduction of the 3'-carbonyl function. Compared to natural (+)-gomphoside, these analogues have the following unique structural features: a steroidal D ring with C8H17-alkyl chain instead of an exocyclic butenolide moiety, a different configuration at bridgehead carbon-14, and lack of a hydroxyl group at this position. The resulting altered chemical properties make them interesting structures for pharmacological evaluation and they are potentially suitable candidates for the development of new inhibitors in cancer therapy.