Inhibitors of sterol synthesis. Chemical syntheses and spectral properties of 26-oxygenated derivatives of 3β-hydroxy-5α-cholest-8(14)-en-15-one and their effects on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells

✍ Scribed by Abdul U. Siddiqui; William K. Wilson; Karen E. Ruecker; Frederick D. Pinkerton; George J. Schroepfer Jr.

• Publisher: Elsevier Science
• Year: 1992
• Tongue: English
• Weight: 974 KB
• Volume: 63
• Category: Article
• ISSN: 0009-3084
• DOI: 10.1016/0009-3084(92)90025-k

✦ Synopsis

26-Oxygenated derivatives of As04)-15-ketosterols have been synthesized from (25R)-3#,26-diacetoxy-5a-cholest-8( )-en-15-one (IX) as part of a program to prepare potential metabolites and analogs of 3/~-hydroxy-5c~-cholest-8( )-en-15-one (I), a potent regulator of cholesterol metabolism. Partial hydrolysis of IX gave a mixture, from which the 3/~,26-diol H and the 26-acetate (XI) and 3/~-acetate (X) monoesters were isolated. Mitsunobu reaction of XI followed by hydrolysis gave (25R)-3a,26-dihydroxy-5~cholest-8( )-en-I 5-one (VI). Oxidation of XI with pyridinium chlorochromate followed by hydrolysis of the acetate gave (25R)-26hydroxy-5~-cholest-8( )-ene-3,15-dione (VII). Oxidation of X with Jones reagent followed by hydrolysis of the acetate gave (25R)-3/~-hydroxy-15-keto-5c~-cholest-8( )-en-26-oic acid 0Na). Jones oxidation of H gave (25R)-3,15-diketo-5~-cholest-8( )-en-26-oic acid (VH). 1H and 13C 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 3hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-KI cells, with a potency comparable to that of I. In contrast, 3ce,26diol VI was less potent than I or VII. The two carboxylic acid analogs IVa and VHI were considerably less potent than VI in lowering the levels of HMG-CoA reductase activity.