Inhibitors of sterol biosynthesis. Synthesis and activities of ring C oxygenated sterols

Abstract

The chemical syntheses of a number of C 27 ring C oxygenated sterols have been pursued to permit evaluation of their activity in the inhibition of sterols biosynthesis in cultured mammalian cells. Thus, 5α-cholest-7-ene-3β,11α-diol, 3α-hydroxy-5α-cholest-9(11)-en-12-one and the previously unreported 11α-hydroxy-5α-cholest-7-en-3-one, 5α-cholest-9(11)-ene-3,12-dione, and 3β-hydroxy-5α-cholest-9(11)-en-12-one have been synthesized. The effects of these compounds on the synthesis of digitonin-precipitable sterols from labeled acetate in mouse L cells and on the levels of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase activity in the same cells have been investigated and compared with previously published data on other ring C oxygenated sterols. 5α-Cholest-7-ene-3β,11α-diol was shown to be the most potent inhibitor of sterol synthesis.