title: Inhibitors of sterol synthesis. Metabolism-based design and construction of a new analog of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one and its effects in cultured mammalian cells and in rats.
abstract: 3 beta-Hydroxy-5 alpha-cholest-8(14)-en-15-one (I) is a potent regulator of cholesterol metabolism. In the present study, the 7 alpha-methyl-25,26,26,26,27,27,27-heptafluoro analog (X) of I has been synthesized with the goal of blocking not only the side chain oxidation of I but also its conversion to cholesterol. X was prepared in seven steps from the known 7 alpha-methyl analog (IX) of I. Treatment of the acetate of IX with a mixture of trifluoroacetic anhydride, hydrogen peroxide, and sulfuric acid gave 3 beta-acetoxy-7 alpha-methyl-24-hydroxy-5 alpha-chol-8(14)-en-15-one (XII) in remarkably high (68%) yield. Dehydration of XII via the orthonitrophenylselenide to the 23-ene, followed by addition of (CF3)2CFI gave (23R)-3 beta-acetoxy-7 alpha-methyl-23-iodo-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (XV). Reductive deiodination of XV with tributyltin hydride, followed by hydrolysis of the acetate gave 3 beta-hydroxy-7 alpha-methyl-25,26,26,26,27,27,27-heptafluoro-5 alpha-cholest-8(14)-en-15-one (X). The F7-7 alpha-methyl-15-ketosterol X lowered the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells with a potency equivalent to that of I. X showed significant hypocholesterolemic action upon oral administration to rats, with a potency far in excess of the 7 alpha-methyl-15-ketosterol IX lacking the F7 substitution. In marked contrast to I, X showed little or no suppression of food consumption in rats. Upon oral administration of X to rats, low levels of X (relative to cholesterol), characterized by chromatographic and gas chromatography-mass spectrometric methodologies, were observed in serum, liver, and small intestine. No material was observed with the expected properties of F7-7-methylcholesterol (or potential intermediates in its possible formation from X). In contrast to I, X lowered serum cholesterol levels at dosages at which no effect on food consumption was observed.
authors.affiliation: Department of Biochemistry, Rice University, Houston, TX 77251, USA.
authors.forename: S
authors.initials: S
authors.lastname: Swaminathan
authors.forename: A U
authors.initials: AU
authors.lastname: Siddiqui
authors.forename: N
authors.initials: N
authors.lastname: Gerst
authors.forename: F D
authors.initials: FD
authors.lastname: Pinkerton
authors.forename: A
authors.initials: A
authors.lastname: Kisic
authors.forename: L J
authors.initials: LJ
authors.lastname: Kim
authors.forename: W K
authors.initials: WK
authors.lastname: Wilson
authors.forename: G J
authors.initials: GJ
authors.lastname: Schroepfer
mesh_terms: D000818:Animals; D000924:Anticholesteremic Agents / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000737:chemistry; D002478:Cells, Cultured; D002783:Cholestenones / Q000138:chemical synthesis* / Q000737:chemistry; D002784:Cholesterol / Q000378:metabolism*; D004032:Diet; D009682:Magnetic Resonance Spectroscopy; D008322:Mammals; D013058:Mass Spectrometry; D051381:Rats
chemical_list: D000924:Anticholesteremic Agents; D002783:Cholestenones; C015073:cholest-8(14)-en-3-ol-15-one; D002784:Cholesterol