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 delta 8(14)-15-ketosterols have been synthesized from (25R)-3 beta,26-diacetoxy-5 alpha-cholest-8(14)-en-15-one (IX) as part of a program to prepare potential metabolites and analogs of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I), a potent regulator of cholesterol metabolism. Partial hydrolysis of IX gave a mixture, from which the 3 beta,26-diol II and the 26-acetate (XI) and 3 beta-acetate (X) monoesters were isolated. Mitsunobu reaction of XI followed by hydrolysis gave (25R)-3 alpha,26-dihydroxy-5 alpha-cholest-8(14)-en-15-one (VI). Oxidation of XI with pyridinium chlorochromate followed by hydrolysis of the acetate gave (25R)-26-hydroxy-5 alpha-cholest-8(14)-ene-3,15-dione (VII). Oxidation of X with Jones reagent followed by hydrolysis of the acetate gave (25R)-3 beta-hydroxy-15-keto-5 alpha-cholest-8(14)-en-26-oic acid (IVa). Jones oxidation of II gave (25R)-3,15-diketo-5 alpha-cholest-8(14)-en-26-oic acid (VII). 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 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in CHO-K1 cells, with a potency comparable to that of I. In contrast, 3 alpha,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.
Siddiqui
A U
AU
Department of Biochemistry and Cell Biology, Rice University, Houston, Texas 77251-1892.
Wilson
W K
WK
Ruecker
K E
KE
Pinkerton
F D
FD
Schroepfer
G J
GJ
D000818:Animals; D016466:CHO Cells / Q000187:drug effects / Q000201:enzymology; D002777:Cholestanols / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006224:Cricetinae; D008401:Gas Chromatography-Mass Spectrometry; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009682:Magnetic Resonance Spectroscopy; D013261:Sterols / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
D002777:Cholestanols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols