title: Synthesis of the antiproliferative agent hippuristanol and its analogues from hydrocortisone via Hg(II)-catalyzed spiroketalization: structure-activity relationship.
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.
authors.affiliation: Département 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.
authors.forename: Ragam
authors.initials: R
authors.lastname: Somaiah
authors.forename: Kontham
authors.initials: K
authors.lastname: Ravindar
authors.forename: Regina
authors.initials: R
authors.lastname: Cencic
authors.forename: Jerry
authors.initials: J
authors.lastname: Pelletier
authors.forename: Pierre
authors.initials: P
authors.lastname: Deslongchamps
mesh_terms: D000818:Animals; D002384:Catalysis; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D012321:DNA-Directed RNA Polymerases / Q000378:metabolism; D006801:Humans; D006854:Hydrocortisone / Q000737:chemistry*; D009682:Magnetic Resonance Spectroscopy; D008628:Mercury / Q000737:chemistry*; D013237:Stereoisomerism; D013261:Sterols / Q000138:chemical synthesis* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D013261:Sterols; C510125:hippuristanol; D012321:DNA-Directed RNA Polymerases; D008628:Mercury; D006854:Hydrocortisone