Inhibitors of sterol synthesis. Characterization of beta,gamma-unsaturated analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells.
Treatment of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (1), a potent regulator of cholesterol metabolism, with perchloric acid in methanol resulted in its partial isomerization to the beta,gamma-unsaturated 15-ketosterols, 3 beta-hydroxy-5 alpha,14 beta-cholest-8-en-15-one (2) and 3 beta-hydroxy-5 alpha,14 beta-cholest-7-en-15-one (3), which were easily separated from 1 by chromatography. Isomers 1, 2, and 3 could be distinguished by their chromatographic retention times as well as by their physical and spectral properties. Reduction of 2 with sodium borohydride gave 5 alpha,14 beta-cholest-8-ene-3 beta,15 beta-diol (4), for which the C-15 configuration was established from the lanthanide-induced shifts of its 3 beta-tert-butyldimethylsilyl ether. 1H and 13C NMR chemical shift differences between 2, 3, and 4 indicated the involvement of variable populations of conformers that differ in the flexible C-D ring system and in the side chain. Compounds 2, 3, and 4 lowered the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells.
Department of Biochemistry, Rice University, Houston, TX 77251-1892.
W K
WK
Wilson
M E
ME
Wheeler
F D
FD
Pinkerton
J
J
St Pyrek
G J
GJ
Schroepfer
D000818:Animals; D002460:Cell Line; D002783:Cholestenones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D003412:Cricetulus; D005260:Female; D006903:Hydroxymethylglutaryl CoA Reductases / Q000096:biosynthesis*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D010053:Ovary / Q000187:drug effects / Q000201:enzymology*
D002783:Cholestenones; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C015073:cholest-8(14)-en-3-ol-15-one; D006903:Hydroxymethylglutaryl CoA Reductases