title: Inhibitors of sterol synthesis. Chemical synthesis and properties of 3 beta-hydroxy-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one and 25,26,26,26,27,27,27-heptafluorocholesterol and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells.
abstract: A side-chain fluorinated delta 8(14)-15-ketosterol has been synthesized from 3 beta-acetoxy-24-hydroxy-5 alpha-chol-8(14)-en-15-one (VII) as part of a program to prepare new analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism. 3 beta-Hydroxy-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (VIII) was prepared in five steps from VII in 38% overall yield. Dehydration of VII via the ortho-nitrophenylselenide to the 23-ene, followed by addition of (CF3)2CFI gave 3 beta-acetoxy-23R-iodo-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one. Reductive deiodination with tributyltin hydride, followed by hydrolysis of the acetate gave VIII. 25,26,26,26,27,27,27-Heptafluorocholest-5-en-3 beta-ol (XXI) was prepared in eight steps in 31% overall yield from 3 alpha,6 alpha-diacetoxy-5 beta-cholanic acid (XIII). Compound XIII was reduced with borane-methyl sulfide to the corresponding 24-hydroxysteroid, which was converted to 3 alpha,6 alpha-diacetoxy-25,26,26,26,27,27,27-heptafluoro-5 beta-cholestane (XVIII) by reactions analogous to those developed for the preparation of VIII from VII. Conversion of XVIII via the 3 alpha,6 alpha-diol to the 3 alpha,6 alpha-ditosylate, followed by heating with potassium acetate in dimethylformamide and subsequent hydrolysis gave XXI. Full 1H and 13C NMR assignments are presented for VIII, XXI, and intermediates involved in their synthesis. 13C NMR assignments for 3 alpha,6 alpha-dihydroxy-5 beta-steroids have been corrected, and stereochemical assignments were established for the side-chain methylene protons of VIII, XXI, and most synthetic intermediates. Compound VIII lowered the levels of HMG-CoA reductase activity in CHO-K1 cells and in HepG2 cells with a potency comparable to that of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I). In contrast, 25,26,26,26,27,27,27-heptafluorocholest-5-en-3 beta-ol had little or no effect on reductase activity in CHO-K1 cells. These combined results indicate that metabolism of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I) to 26- and 25-oxygenated species is not required for the suppressive action of I on the levels of HMG-CoA reductase activity in CHO-K1 cells and HepG2 cells.
authors.affiliation: Department of Biochemistry, Rice University, Houston, TX 77251.
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
authors.forename: W K
authors.initials: WK
authors.lastname: Wilson
authors.forename: F D
authors.initials: FD
authors.lastname: Pinkerton
authors.forename: N
authors.initials: N
authors.lastname: Gerst
authors.forename: M
authors.initials: M
authors.lastname: Ramser
authors.forename: G J
authors.initials: GJ
authors.lastname: Schroepfer
mesh_terms: D000818:Animals; D016466:CHO Cells / Q000201:enzymology; D002783:Cholestenones / Q000138:chemical synthesis* / Q000494:pharmacology; D002784:Cholesterol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D002845:Chromatography; D006224:Cricetinae; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D013261:Sterols / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D005466:Fluorocarbons
chemical_list: D002783:Cholestenones; D002784:Cholesterol; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols; C084394:3-hydroxy-25,26,26,26,27,27,27-heptafluoro-5-cholest-8(14)-en-15-one; D005466:Fluorocarbons; C084396:25,26,26,26,27,27,27-heptafluorocholesterol