Inhibitors of sterol synthesis. Synthesis and spectral properties of 3 beta-hydroxy-24-dimethylamino-5 alpha-chol-8(14)-en-15-one and its effects on HMG-CoA reductase activity in CHO-K1 cells.
A simple, three-step synthesis of the 25-aza analog of 3 beta-hydroxy-5 alpha-cholest-8(14)-en-15-one (I) is described. Treatment of 3 beta-acetoxy-24-hydroxy-5 alpha-chol-8(14)-en-15-one (III) with 1.75 equivalents of tosyl chloride in pyridine for 24 h at 5 degrees C gave 3 beta-acetoxy-24-tosyloxy-5 alpha-chol-8(14)-en-15-one (IV). In contrast, treatment of III with 3.95 equivalents of tosyl chloride in pyridine for 12 h at 48 degrees C gave 3 beta-acetoxy-24-chloro-5 alpha-chol-8(14)-en-15-one (V). Treatment of IV with dimethylamine in dioxane yielded 3 beta-acetoxy-24-dimethylamino-5 alpha-chol-8(14)-en-15-one (VI). Hydrolysis of VI with LiOH.H2O in methanol gave 3 beta-hydroxy-24-dimethylamino-5 alpha-chol-8(14)-en-15-one (VII). 1H- and 13C-NMR assignments are presented for compounds IV-VII. The 25-aza analog (VII) of the 15-ketosterol (I), at a concentration of 1.0 microM, caused a 47% lowering of the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in Chinese hamster ovary cells.
Herz
J E
JE
Department of Biochemistry and Cell Biology, Rice University, Houston, TX 77251-1892.
Wilson
W K
WK
Pinkerton
F D
FD
Schroepfer
G J
GJ
D000818:Animals; D002460:Cell Line; D002770:Cholenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002855:Chromatography, Thin Layer; D006903:Hydroxymethylglutaryl CoA Reductases / Q000187:drug effects*; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure
D002770:Cholenes; C074570:3-hydroxy-24-dimethylaminochol-8(14)-en-15-one; D006903:Hydroxymethylglutaryl CoA Reductases