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 language | English (US) |
|---|---|
| Pages (from-to) | 247-261 |
| Number of pages | 15 |
| Journal | Journal of Lipid Research |
| Volume | 30 |
| Issue number | 2 |
| State | Published - 1989 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Endocrinology
Cite this
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 journal › Article
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TY - JOUR
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.
UR - http://www.scopus.com/inward/record.url?scp=0024552874&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0024552874&partnerID=8YFLogxK
M3 - Article
C2 - 2715729
AN - SCOPUS:0024552874
VL - 30
SP - 247
EP - 261
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 2
ER -