Abstract
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.
Highlights
The chemical syntheses of anumber of 14a- sis (1 -4)
We have previously reported that a large number of 15-oxygenated sterols are potentinhibitors of sterol biosynthesis in L cells and in primarycultures of fetal mouse liver cells (22,29,30,33,36-38)
The inhibition of sterol synthesis by these compounds was associated with areduction in the levelsof HMGCoA reductase activity
Summary
The chemical syntheses of anumber of 14a- sis (1 -4) This inhibitionof sterol synthesis has been hydroxymethyl sterols andl4a-hydroxymethyl- 15a-hy- demonstrated to be associated with a suppression of droxysterols and their derivatives have been pursued to permit evaluation of their activity in the inhibition of sterol biosynthesis in animal cells in culture. Described are the activity of the key regulatory enzyme HMG-CoA reductase Some of these inhibiting sterols are either chemical syntheses of 7a,8a-epoxy-l4a-methyl-5a-choles- established or possible intermediates in the conversion tan-3/3,15a-diol, 14a-methyl-5a-cholestan-3/3,7a,15a-triolo,f cholesterol tobile acids or to steroid hormonesand. 3/3-01, and 7a,32-epoxy-14a-methy1-5a-cholestan-3/3-oon[1] generallybeenconsidered that the first step in the the synthesis of digitonin-precipitable sterols and on levels enzymatic removal of each of the“extra” methyl of HMG-CoA reductase activity in L cells and in primary groups of lanosterol is via an initial oxidation to yield cultures of fetal mouse liver cells havebeen investigated.
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