Inhibitors of sterol synthesis. Chemical syntheses, properties and effects of 4,4-dimethyl-15-oxygenated sterols on sterol synthesis and on 3-hydroxy-3-methylglutaryl coenzyme A reductase activity in cultured mammalian cells

Abstract

The chemical syntheses of a number of 4,4-dimethyl substituted 15-oxygenated sterols have been pursued to permit evaluation of their activity in the inhibition of the biosynthesis of cholesterol and other biological effects. Described herein are the first chemical syntheses of 4,4-dimethyl-14α-ethyl-5α-cholest-7-en-3β-ol-15-one, 3β,15α-diacetoxy-4,4-dimethyl-14α-ethyl-5α-cholest-7-ene, 3β-acetoxy-4,4-dimethyl-14α-ethyl-5α-cholest-7-en-15β-ol, 4,4-dimethyl-14α-ethyl-5α-cholest-7-ene-3β,15α-diol, 4,4-dimethyl-14α-ethyl-5α-cholest-7-ene-3β,15β-diol, 4,4-dimethyl-14α-ethyl-5α-cholest-7-en-15α-ol-3-one, 3β-benzoyloxy-4,4-dimethyl-5α-cholest-8(14)-ene-7α,15α-diol, 7α,15α-diacetoxy-3β-benzoyloxy-4,4-dimethyl-5α-cholest-8(14)-ene, 4,4-dimethyl-5α-cholest-8(14)-en-3β-ol-15-one and 3 β,7 α,15 α-tri- o-bromobenzoyloxy-5 α-cholest-8(14)-ene. Also prepared for use in the biological experiments were 4,4-dimethyl-5α-cholest-7-ene-3β,15α-diol, 4,4-dimethyl-5α-cholest-8-ene-3β,15α-diol and 4,4-dimethyl-5α-cholest-8(14)-ene-3β,7α,15α-triol. The effects of twelve 4,4-dimethyl substituted 15-oxygenated sterols and of four 4,4-dimethyl substituted 32-oxygenated sterols on sterol synthesis and on the level of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity were evaluated in mouse L cells. With the exception of 4,4-dimethyl-5α-cholest-8(14)-ene-3β,7α,15α-triol, all of the 4,4-dimethyl substituted 15-oxygenated sterols caused a 50% inhibition of sterol synthesis at less than 10 −6 M and six of the 4,4-dimethyl substituted 15-oxygenated sterols caused a 50% inhibition of sterol synthesis at less than 10 −7 M. 4,4-Dimethyl-14α-ethyl-5α-cholest-7-ene-3β,15α-diol caused a 50% decrease in sterol synthesis at 10 −8 M. The potencies of the 4,4-dimethyl substituted 15-oxygenated and C-32-oxygenated sterols with respect to inhibition of sterol synthesis and suppression of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity have been compared with those of the corresponding sterols lacking the 4,4-dimethyl substitution.