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J Med Chem. 2014 Mar 27;57(6):2511-23. doi: 10.1021/jm401799j. Epub 2014 Mar 11.

Synthesis of the antiproliferative agent hippuristanol and its analogues from hydrocortisone via Hg(II)-catalyzed spiroketalization: structure-activity relationship.

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  • 1Département de Chimie, Faculté des Sciences et de Génie, Pavillon Alexandre-Vachon, Université Laval , 1045, Avenue de la Médecine, Ville de Québec, Québec, G1V 0A6, Canada.

Abstract

An efficient synthesis of hippuristanol (1), a marine-derived highly potent antiproliferative steroidal natural product, and nine closely related analogues has been accomplished from the commercially available hydrocortisone utilizing Hg(II)-catalyzed spiroketalization of 3-alkyne-1,7-diol motif as a key strategy. This practical synthetic sequence furnished 1 in 11% overall yield from hydrocortisone in 15 linear steps. Modifications to the parent molecule 1 encompassed changing the functional groups on rings A and E. Each analogue was screened for their effects on inhibition of cap-dependent translation, and the assay results were used to establish structure-activity relationships. These results suggest that the stereochemistry and all substituents of spiroketal portion (rings E and F) and C3-α and C11-β hydroxyl functional groups on rings A and C, respectively, are critical for the inhibitory activity of natural product 1.

PMID:
24588834
[PubMed - indexed for MEDLINE]
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