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Journal of Lipid Research, Vol 36, 767-786, Copyright © 1995 by Lipid Research, Inc.

ARTICLES

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

S Swaminathan, AU Siddiqui, N Gerst, FD Pinkerton, A Kisic, LJ Kim, WK Wilson and GJ Schroepfer Jr
Department of Biochemistry, Rice University, Houston, TX 77251, USA.

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.
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				G. J. Schroepfer Jr. Oxysterols: Modulators of Cholesterol Metabolism and Other Processes Physiol Rev, January 1, 2000; 80(1): 361 - 554. [Abstract] [Full Text] [PDF]