title: Inhibitors of sterol synthesis. A highly efficient and specific side-chain oxidation of 3 beta-acetoxy-5 alpha-cholest-8(14)-en-15-one for construction of metabolites and analogs of the 15-ketosterol.
abstract: As part of a program directed towards the chemical syntheses of potential metabolites and analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism, several routes have been explored for the preparation of 3 beta-hydroxy-15-keto-5 alpha-chol-8(14)-en-24-oic acid (IV). These investigations led to a remarkably specific and efficient side-chain oxidation of I. For example, treatment of the acetate of I with a mixture of trifluoroacetic anhydride, hydrogen peroxide, and sulfuric acid for 3.5 h at -2 degrees C gave a crude product consisting of 3 beta-acetoxy-24-trifluoroacetoxy-5 alpha-chol-8(14)-en-15-one (XI), 3 beta-acetoxy-24-hydroxy-5 alpha-chol-8(14)-en-15-one (XII), and 3 beta, 24-diacetoxy-5 alpha-chol-8(14)-en-15-one (XIII) in yields of 58%, 8%, and 3%, respectively, by HPLC analysis. XI was readily hydrolyzed to XII upon treatment with triethylamine in methanol at room temperature. Oxidation of XII with Jones reagent gave 3 beta-acetoxy-15-keto-5 alpha-chol-8(14)-en-24-oic acid (XVIII) from which its methyl ester (IX) was prepared by treatment with diazomethane. Mild alkaline hydrolysis of XVIII gave the 3 beta-hydroxy-delta 8(14)-15-keto C24 acid (IV). Hydrolysis of the crude product of the side-chain oxidation with K2CO3 in methanol gave 3 beta,24-dihydroxy-5 alpha-chol-8(14)-en-15-one (XIV) which was oxidized with Jones reagent to yield 3,15-diketo-5 alpha-chol-8(14)-en-24-oic acid (XV). Treatment of XV with diazomethane gave its methyl ester (XVI) which, upon controlled reduction with NaBH4, yielded methyl 3 beta-hydroxy-15-keto-5 alpha-chol-8(14)-en-24-oate (XVII). Compound IX was also prepared by an independent route. Full 1H and 13C NMR assignments are presented for 12 new compounds. IV caused a approximately 56% reduction of the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells at a concentration of 2.5 microM. In contrast, the corresponding 3,15-diketo acid XV had no detectable effect on reductase activity under the same conditions.
authors.affiliation: Department of Biochemistry, Rice University, Houston, TX 77251.
authors.forename: J E
authors.initials: JE
authors.lastname: Herz
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
authors.forename: F D
authors.initials: FD
authors.lastname: Pinkerton
authors.forename: W K
authors.initials: WK
authors.lastname: Wilson
authors.forename: G J
authors.initials: GJ
authors.lastname: Schroepfer
mesh_terms: D000089:Acetic Anhydrides; D000818:Animals; D016466:CHO Cells; D002770:Cholenes / Q000737:chemistry; D002783:Cholestenones / Q000737:chemistry / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D006224:Cricetinae; D005463:Fluoroacetates; D006861:Hydrogen Peroxide / Q000378:metabolism; D006903:Hydroxymethylglutaryl CoA Reductases / Q000378:metabolism; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D010084:Oxidation-Reduction; D013464:Sulfuric Acids / Q000378:metabolism; D014269:Trifluoroacetic Acid / Q000378:metabolism
chemical_list: D000089:Acetic Anhydrides; D002770:Cholenes; D002783:Cholestenones; D005463:Fluoroacetates; D013464:Sulfuric Acids; C076701:3-hydroxy-15-keto-chol-8(14)-en-24-oic acid; C076704:3-acetoxycholest-8(14)-en-15-one; C017958:trifluoroacetic anhydride; D002784:Cholesterol; D006861:Hydrogen Peroxide; D014269:Trifluoroacetic Acid; D006903:Hydroxymethylglutaryl CoA Reductases; C033158:sulfuric acid