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

H. S. Kim, W. K. Wilson, D. H. Needleman, F. D. Pinkerton, D. K. Wilson, F. A. Quiocho, G. J. Schroepfer

Research output: Contribution to journalArticle

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Abstract

3β-Hydroxy-5α-cholest-8(14)-en-15-one (I) is a potent inhibitor of sterol synthesis with significant hypocholesterolemic activity. (25R)-3β,26-Dihydroxy-5α-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-3β,26-diol 3β,26-dibenzoate which, upon allylic bromination followed by dehydrobromination, gave (25R)-cholesta-5,7-diene-3β,26-diol 3β,26-dibenzoate. Hydrogenation-isomerization of the Δ5,7-3β,26-dibenzoate to (25R)-5α-cholest-8(14)-ene-3β,26-diol 3β,26-bis(cyclohexanecarboxylate) followed by controlled oxidation with CrO3-dimethylpyrazole gave (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one 3β,26-bis(cyclohexanecarboxylate). Acid hydrolysis of the Δ(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.

Original languageEnglish (US)
Pages (from-to)247-261
Number of pages15
JournalJournal of Lipid Research
Volume30
Issue number2
StatePublished - 1989
Externally publishedYes

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Diosgenin
Sterols
Metabolites
Bioactivity
Hydrogenation
Liver Mitochondrion
Esterification
Halogenation
Microsomes
Cultured Cells
Oxidoreductases
Mitochondria
Hydrolysis
Cholesterol
X-Rays
Isomerization
Liver
Acids
Byproducts
Rats

ASJC Scopus subject areas

  • Endocrinology

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Inhibitors of sterol synthesis. Chemical synthesis, structure, and biological activities of (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one, a metabolite of 3β-hydroxy-5α-cholest-8(14)-en-15-one. / Kim, H. S.; Wilson, W. K.; Needleman, D. H.; Pinkerton, F. D.; Wilson, D. K.; Quiocho, F. A.; Schroepfer, G. J.

In: Journal of Lipid Research, Vol. 30, No. 2, 1989, p. 247-261.

Research output: Contribution to journalArticle

Kim, H. S. ; Wilson, W. K. ; Needleman, D. H. ; Pinkerton, F. D. ; Wilson, D. K. ; Quiocho, F. A. ; Schroepfer, G. J. / Inhibitors of sterol synthesis. Chemical synthesis, structure, and biological activities of (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one, a metabolite of 3β-hydroxy-5α-cholest-8(14)-en-15-one. In: Journal of Lipid Research. 1989 ; Vol. 30, No. 2. pp. 247-261.
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abstract = "3β-Hydroxy-5α-cholest-8(14)-en-15-one (I) is a potent inhibitor of sterol synthesis with significant hypocholesterolemic activity. (25R)-3β,26-Dihydroxy-5α-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-3β,26-diol 3β,26-dibenzoate which, upon allylic bromination followed by dehydrobromination, gave (25R)-cholesta-5,7-diene-3β,26-diol 3β,26-dibenzoate. Hydrogenation-isomerization of the Δ5,7-3β,26-dibenzoate to (25R)-5α-cholest-8(14)-ene-3β,26-diol 3β,26-bis(cyclohexanecarboxylate) followed by controlled oxidation with CrO3-dimethylpyrazole gave (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one 3β,26-bis(cyclohexanecarboxylate). Acid hydrolysis of the Δ(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.",
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T1 - Inhibitors of sterol synthesis. Chemical synthesis, structure, and biological activities of (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one, a metabolite of 3β-hydroxy-5α-cholest-8(14)-en-15-one

AU - Kim, H. S.

AU - Wilson, W. K.

AU - Needleman, D. H.

AU - Pinkerton, F. D.

AU - Wilson, D. K.

AU - Quiocho, F. A.

AU - Schroepfer, G. J.

PY - 1989

Y1 - 1989

N2 - 3β-Hydroxy-5α-cholest-8(14)-en-15-one (I) is a potent inhibitor of sterol synthesis with significant hypocholesterolemic activity. (25R)-3β,26-Dihydroxy-5α-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-3β,26-diol 3β,26-dibenzoate which, upon allylic bromination followed by dehydrobromination, gave (25R)-cholesta-5,7-diene-3β,26-diol 3β,26-dibenzoate. Hydrogenation-isomerization of the Δ5,7-3β,26-dibenzoate to (25R)-5α-cholest-8(14)-ene-3β,26-diol 3β,26-bis(cyclohexanecarboxylate) followed by controlled oxidation with CrO3-dimethylpyrazole gave (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one 3β,26-bis(cyclohexanecarboxylate). Acid hydrolysis of the Δ(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.

AB - 3β-Hydroxy-5α-cholest-8(14)-en-15-one (I) is a potent inhibitor of sterol synthesis with significant hypocholesterolemic activity. (25R)-3β,26-Dihydroxy-5α-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-3β,26-diol 3β,26-dibenzoate which, upon allylic bromination followed by dehydrobromination, gave (25R)-cholesta-5,7-diene-3β,26-diol 3β,26-dibenzoate. Hydrogenation-isomerization of the Δ5,7-3β,26-dibenzoate to (25R)-5α-cholest-8(14)-ene-3β,26-diol 3β,26-bis(cyclohexanecarboxylate) followed by controlled oxidation with CrO3-dimethylpyrazole gave (25R)-3β,26-dihydroxy-5α-cholest-8(14)-en-15-one 3β,26-bis(cyclohexanecarboxylate). Acid hydrolysis of the Δ(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.

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