Schroepfer G J, Parish E J, Pascal R A, Kandutsch A A
J Lipid Res. 1980 Jul;21(5):571-84.
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.
已开展多种14α-羟甲基甾醇和14α-羟甲基-15α-羟基甾醇及其衍生物的化学合成研究，以便评估它们对培养的动物细胞中甾醇生物合成的抑制活性。本文描述了7α,8α-环氧-14α-甲基-5α-胆甾烷-3β,15α-二醇、14α-甲基-5α-胆甾烷-3β,7α,15α-三醇、3β,15α-二乙酰氧基-14α-甲基-5α-胆甾烷-7α-醇、3β,15α-二乙酰氧基-7α,32-环氧-14α-甲基-5α-胆甾烷、14α-羟甲基-5α-胆甾-6-烯-3β,15α-二醇、14α-羟甲基-5α-胆甾-7-烯-3β,15α-二醇、7α,32-环氧-14α-甲基-5α-胆甾烷-3β,15α-二醇、14α-羟甲基-5α-胆甾-6-烯-3-酮、14α-羟甲基-5α-胆甾-7-烯-3-酮以及14α-羟甲基-5α-胆甾-7-烯-15α-醇-3-酮的化学合成。已研究了上述化合物中的八种以及14α-羟甲基-5α-胆甾-8-烯-3β-醇、14α-羟甲基-5α-胆甾-7-烯-3β-醇、14α-羟甲基-5α-胆甾-6-烯-3β-醇和7α,32-环氧-14α-甲基-5α-胆甾烷-3β-醇对洋地黄皂苷可沉淀甾醇合成以及对L细胞和原代培养的胎鼠肝细胞中HMG-CoA还原酶活性水平的影响。发现所有的14α-羟甲基甾醇和14α-羟甲基-15α-羟基甾醇都是甾醇合成的有效抑制剂，并能降低这些细胞中HMG-CoA还原酶的活性水平。由于胆固醇的14α-甲基甾醇前体的14α-甲基羟基化可被视为胆固醇生物合成中的一个必要步骤，14α-羟甲基甾醇是胆固醇生物合成的有效抑制剂并能导致HMG-CoA还原酶活性水平降低这一发现增加了如下可能性，即胆固醇的氧化甾醇前体，如14α-羟甲基甾醇，可能在胆固醇合成的调节以及在依赖甲羟戊酸和甾醇形成的过程的调节中发挥重要作用。
