Inhibition of sterol biosynthesis in animal cells by 14 alpha-hydroxymethyl sterols.
The chemical syntheses of a number of 14 alpha-hydroxymethyl sterols and 14 alpha -hydroxymethyl-15 alpha-hydroxysterols and their derivatives have been pursued to permit evaluation of their activity in the inhibition of sterol biosynthesis in animal cells in culture. Described herein are chemical syntheses of 7 alpha,8 slpha-epoxy-14 alpha-methyl-5 alpha-cholestan-3 beta,15 alpha-diol, 14 alpha-methyl-5 alpha-cholestan-3 beta,7 alpha,15 alpha-triol, 3 beta,15 alpha-diacetoxy-14 alpha-methyl-5 alpha-cholestan-7 alpha-ol, 3 beta,15 alpha-diacetoxy-7 alpha,32-epoxy-14 alpha-methyl-5 alpha-cholestane, 14 alpha-hydroxymethyl-5 alpha-cholest-6-en-3 beta,15 alpha-diol, 14 alpha-hydroxymethyl-5 alpha-cholest-7-en-3 beta,15 alpha-diol, 7 alpha,32-epoxy-14 alpha-methyl-5 alpha-cholestan-3 beta,15 alpha-diol, 14 alpha-hydroxymethyl-5 alpha-cholest-6-en-3-one, 14 alpha-hydroxymethyl-5 alpha-cholest-7-en-3-one, and 14 alpha-hydroxymethyl-5 alpha-cholets-7-en-15 alpha-ol-3-one. The effects of eight of the above compounds and of 14 alpha-hydroxymethyl-5 alpha-cholest-8-en-3 beta-ol, 14 alpha-hydroxymethyl-5 alpha-cholest-7-en-3 beta-ol, 14 alpha-hydroxymethyl-5 alpha-cholest-6-en-3 beta-ol, and 7 alpha,32-epoxy-14 alpha-methyl-5 alpha-cholestan-3 beta-ol on the synthesis of digitonin-precipitalbe sterols and on levels of HMG-CoA reductase activity in L cells and in primary cultures of fetal mouse liver cells have been investigated. All of the 14 alpha-hydroxymethyl sterols and 14 alpha-hydroxymethyl-15 alpha-hydroxysterols were found to be potent inhibitors of sterol synthesis and to reduce the levels of HMG-CoA reductase activity in these cells. Since hydroxylation of the 14 alpha-methyl group of 14 alpha-methyl sterol precursors of cholesterol can be considered as an obligatory step in the biosynthesis of cholesterol, the finding that 14 alpha-hydroxymethyl sterols are potent inhibitors of cholesterol biosynthesis and cause a reduction in the levels of HMG-CoA reductase activity raises the possibility that oxygenated sterol precursors of cholesterol, such as 14 alpha-hydroxymethyl sterols, may play an important role in the regulation of cholesterol synthesis and in the regulation of processes dependent upon mevalonate and sterol formation.
D000818:Animals; D002478:Cells, Cultured; D005333:Fetus; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007700:Kinetics; D007739:L Cells; D008099:Liver / Q000201:enzymology; D051379:Mice; D013261:Sterols / Q000096:biosynthesis*; D013329:Structure-Activity Relationship
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D013261:Sterols