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. H-1 and C-13 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.