Inhibitors of sterol synthesis. Chemical synthesis, structure, and biological activities of (25R)-3 beta,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one, a metabolite of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one

• Published in: Journal of lipid research 1989-02, Vol.30 (2), p.247-261
• Main Authors: Kim, H S, Wilson, W K, Needleman, D H, Pinkerton, F D, Wilson, D K, Quiocho, F A, Schroepfer, Jr, G J
• Format: Article
• Language: English
• Subjects: Animals; Anticholesteremic Agents - chemical synthesis; Anticholesteremic Agents - pharmacology; Cell Line; Cholesterol - analogs & derivatives; Cholesterol - chemical synthesis; Cholesterol - pharmacology; Crystallography; Diosgenin; Hydroxymethylglutaryl CoA Reductases - metabolism; Jejunum - metabolism; Microsomes - metabolism; Rats; Sterol O-Acyltransferase - metabolism; Sterols - chemical synthesis; Sterols - pharmacology; Temperature
• ISSN: 0022-2275
• DOI: 10.1016/S0022-2275(20)38385-1

3 beta-Hydroxy-5 alpha-cholest-8(14)-en-15-one (I) is a potent inhibitor of sterol synthesis with significant hypocholesterolemic activity. (25R)-3 beta,26-Dihydroxy-5 alpha-cholest-8(14)-en-15-one (II) has been shown to be a major metabolite of I after incubation with rat liver mitochondria. Described herein is the chemical synthesis of II from diosgenin. As part of this synthesis, improved conditions are described for the conversion of diosgenin to (25R)-26-hydroxycholesterol. Benzoylation of the latter compound gave (25R)-cholest-5-ene-3 beta,26-diol 3 beta,26-dibenzoate which, upon allylic bromination followed by dehydrobromination, gave (25R)-cholesta-5,7-diene-3 beta,26-diol 3 beta,26-dibenzoate. Hydrogenation-isomerization of the delta 5.7-3 beta,26-dibenzoate to (25R)-5 alpha-cholest-8(14)-ene-3 beta,26-diol 3 beta,26-bis(cyclohexanecarboxylate) followed by controlled oxidation with CrO3-dimethylpyrazole gave (25R)-3 beta,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one 3 beta,26-bis(cyclohexanecarboxylate). Acid hydrolysis of the delta 8(14)-15-ketosteryl diester gave II. 13C NMR assignments are given for all synthetic intermediates and several major reaction byproducts. The structure of II was unequivocally established by X-ray crystal analysis. II was found to be highly active in the suppression of the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase in cultured mammalian cells and to inhibit oleoyl coenzyme A-dependent esterification of cholesterol in jejunal microsomes.