George J. Schroepfer

Chemical synthesis, spectral properties, and chromatography of 4α-methyl and 4β-methyl isomers of (24R)-24-ethyl-5α-cholestan-3β-ol and (24S)-24-ethyl-cholesta-5,22-dien-3β-ol

Abstract Described herein are chemical syntheses of the following compounds: 4-methyl-(24S)-24-ethyl-cholesta-4,22-dien-3-one, 4,4-dimethyl-(24S)-24-ethyl-cholesta-5, 22-dien-3-one, 4β-methyl-(24R)-24-ethyl-5α-cholestan-3β-ol, 4α-methyl-(24R)-24-ethyl-5α-cholestan-3β-ol, 4α-methyl-(24S)-24-ethyl-5α-cholest-22-en-3β-ol, 4-methyl-6β-bromo-(24S)-24-ethyl-cholesta-4, 22-dien-3-one, 4α-raethyl-(24S)-24-ethyl-cholesta-5, 22-dien-3β-ol, 4α,5α-epoxy-(24S)-24-ethyl-cholesta-4,22-dien-3β-yl acetate, 4β-methyl-(24S)-24-ethyl-cholest-22-en-3β,5α-diol, 4β-methyl-5α-hydroxy-(24S)-24-ethyl-cholest-22-en-3β-yl acetate, 4β-methyl-(24S)-24-ethyl-cholesta-5, 22-dien-3β-yl acetate and 4β-methyl-(24S)-24-ethyl-cholesta-5, 22-dien-3β-ol. Chromatographic, nuclear magnetic resonance, and mass spectral data are presented for the compounds under consideration.

Inhibitors of sterol synthesis. Hypocholesterolemic action of dietary 5α-cholest-8(14)-en-3β-ol-15-one in rats and mice☆

Abstract 5α-Cholest-8(14)-en-3β-ol-15-one, at a level of 0.1% in a low cholesterol diet has been shown to have a profound hypocholesterolemic effect in rats. In one experiment the mean serum cholesterol level (mg per 100 ml ± S.E.M.) decreased from 71.2 ± 0.9 to 36.9 ± 3.3 after 7 days on the diet. In a second experiment the mean serum cholesterol value decreased from 86.4 ± 1.2 to 33.4 ± 3.9 after 8 days on the ketone-containing diet. The effects of the 15-ketosterol on serum cholesterol levels were significantly (p

Sterol synthesis. Chemical synthesis of 3β-benzoyloxy -14α, 15α-epoxy-5α-cholest-7-ene, a key intermediate in the synthesis of 15-oxygenated sterols☆

Abstract 3β-Benzoyloxy-14α, 15α-epoxy-5α-cholest-7-ene was obtained in 96% yield upon treatment of 3β-benzoyloxy-5α-cholesta-7, 14-diene with m -chloroperbenzoic acid. The Δ 7 -14 α , 15α-epoxy-steryl ester provides a useful intermediate for the syntheses of sterols with an oxygen function at carbon atom 15. For example, treatment of 3β-benzoyloxy-14α, 15α-epoxy-5α-cholest-7-ene with methanolic hydrochloric acid gave 3β-benzoyloxy-5α-cholest-8(14)-en-15-one in 82% yield.

Sterol composition of bovine retinal rod outer segment membranes and whole retinas

The sterol composition of bovine retinal rod outer segment membranes and whole retinas was studied by detailed chromatographic analyses. Cholesterol represented at least 98% of the total 3 beta-monohydroxy sterols of rod outer segment membranes, accounting for 1.68 +/- 0.15% of the dry weight. Whole retinas contained 1.76 +/- 0.29% cholesterol by dry weight, representing at least 99% of the total 3 beta-monohydroxy sterols. Trace amounts of a component having the chromatographic properties of 5 alpha-cholestan-3 beta-ol were found in rod outer segment membranes and whole retinas. Very small amounts of a component having the chromatographic properties of 5 alpha-cholest-7-en-3 beta-ol were found in whole retinas, but not in rod outer segment membranes. The molar ratio of cholesterol to rhodopsin in bovine rod outer segment membranes was approximately 4.7. Cholesterol accounted for only 5-7 mol% of total rod outer segment membrane lipids.

Inhibitors of sterol synthesis. Dietary administration of 5α-cholest-8(14)-en-3β-ol-15-one inhibits the intestinal absorption of cholesterol in lymph-cannulated rats☆

The effect of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of cholesterol synthesis with marked hypocholesterolemic activity, on the intestinal absorption of exogenous cholesterol has been studied in lymph-cannulated rats. Administration of the 15-ketosterol at a level of 0.05% in a rat chow diet for 10 days was associated with a marked decrease (-64%) in the absorption of cholesterol.

Enzymatic formation and chemical synthesis of an active metabolite of 3β-hydroxy-5α-cholest-8(14)-en-15-one, a potent regulator of cholesterol metabolism☆

The enzymatic (rat liver mitochondria) conversion of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one to 5 alpha-cholest-8(14)-ene-3 beta,26-diol-15-one is described. The enzymatic product was judged, on the basis of IH and 13C NMR studies, to be a 4:1 mixture of its 25R and 25S isomers. (25R)-5 alpha-Cholest-8(14)-ene-3 beta,26-diol-15-one was prepared through a five-step synthesis from (25R)-26-hydroxycholesterol. The (25R) isomer of the new compound was found to be highly active in the suppression of the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells and to inhibit the esterification of cholesterol in jejunal microsomes.

5α-Cholest-8(14)-EN-3β-OL-15-one. A competitive substrate for acyl coenzyme a:Cholesterol acyl transferase*

Summary 5α-Cholest-8(14)-en-3β-ol-15-one, a potent inhibitor of cholesterol biosynthesis with hypocholesterolemic activity, has been found to serve as an efficient substrate for acyl CoA:cholesterol acyl transferase of rat hepatic and jejunal microsomes and to inhibit the esterification of cholesterol. Concentrations required to give 50% inhibition of cholesterol ester formation in liver and jejunal microsomes were ∼10 μM and ∼3 μM, respectively.

Concerning the chemical synthesis of 3β-hydroxy-5α-cholest-8(14)-en-15-one, a novel regulator of cholesterol metabolism

Abstract A four-step synthesis of 3β-hydroxy-5α-cholest-8(14)-en-15-one ( I ) from 7-dehydrocholesterol is described. This synthesis, which is efficient and suitable for kilogram scale work, was carried out in a 33% overall, average yield (39% overall best yield). A major byproduct of the hydrolysis of 3β-benzoyloxy-14α,15α-epoxy-5α-cholest-7-ene to I was found to be the ring C aromatic sterol 12-methyl-18-nor-5α-cholesta-8,11,13-trien-3β-ol. Several other intermediates and byproducts of these reactions were also identified. All new sterols were characterized by 1 H- and 13 C-NMR.

Sterol synthesis: Medium-pressure chromatography of C27 sterol precursors of cholesterol on alumina-silver nitrate columns

Abstract A chromatographic method involving medium-pressure liquid chromatography on alumina impregnated with silver nitrate is described for the separation of a series of closely related C27 sterol precursors of cholesterol differing only in the number and location of olefinic double bonds. The features of the described system are compared with those of previously described thin-layer, gas-liquid, gravity column, and high-pressure liquid chromatographic methods.

Inhibitors of sterol synthesis. Effect of dietary 5α-cholest-8(14)-EN-3β-OL-15-one on acat activity of jejunal microsomes of the rat

Dietary administration (0.1% in a chow diet for 8 days) of 5 alpha-cholest-8(14)-en-3 beta-ol-15-one, a potent inhibitor of sterol biosynthesis with marked hypocholesterolemic action, to rats caused a 77% reduction in the levels of acyl co-enzyme A:cholesterol acyl transferase activity of jejunal microsomes relative to those observed in pair-fed control animals. No differences were observed in mean levels of cholesterol concentration in jejunal microsomes of experimental and pair-fed control animals.