INHIBITORS OF STEROL SYNTHESIS - CHEMICAL SYNTHESES AND SPECTRAL PROPERTIES OF 26-OXYGENATED DERIVATIVES 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

26-Oxygenated derivatives of DELTA8(14)-15-ketosterols have been synthesized from (25R)-3beta,26-diacetoxy-5alpha-cholest-8(14)-en-15-one (IX) as part of a program to prepare potential metabolites and analogs of 3beta-hydroxy-5alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism. Partial hydrolysis of IX gave a mixture, from which the 3beta,26-diol II and the 26-acetate (XI) and 3beta-acetate (X) monoesters were isolated. Mitsunobu reaction of XI followed by hydrolysis gave (25R)-3alpha,26-dihydroxy-5alpha-cholest-8(14)-en-15-one (VI). Oxidation of XI with pyridinium chlorochromate followed by hydrolysis of the acetate gave (25R)-26-hydroxy-5alpha-cholest-8(14)-ene-3,15-dione (VIII). Oxidation of X with Jones reagent followed by hydrolysis of the acetate gave (25R)-3beta-hydroxy-15-keto-5alpha-cholest-8(14)-en-26-oic acid (IVa). Jones oxidation of II gave (25R)-3,15-diketo-5alpha-cholest-8(14)-en-26-oic acid (VII). H-1 and C-13 nuclear magnetic resonance assignments and analyses of mass spectral fragmentation data are presented for each of the new compounds and their derivatives. The 3,15-diketone VII was found to be highly active in lowering the levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells, with a potency comparable to that of I. In contrast, 3alpha,26-diol VI was less potent than I or VII. The two carboxylic acid analogs IVa and VIII were considerably less potent than VI in lowering the levels of HMG-COA reductase activity.