Chemical Synthesis of Ring C oxygenated Derivatives of Cholesterol and their Inhibition of Sterol Biosynthesis

Chemical synthesis of oxygenated derivatives of cholesterol and lanosterol, have been shown to produce oxysterols with significant activity as inhibitors of 3-hydroxy-3methylglutaryl (HMG) CoA reductase, a key regulatory enzyme in sterol biosynthesis. We now reports the detailed chemical synthesis of new ring C oxysterols which have been evaluated as inhibitors of HMG-CoA reductase. The starting material was 3benzoyloxy-9,11-epoxy-5-cholest-7-ene (1), whose structure has been confirmed by X-ray crystallographic analysis. Chemical modification of 1 produced 9,11epoxy-5-cholest-7-en-3-ol (2), the 9-H (natural) isomers 5,9-cholest-7-en3,11-diol (3) and 5,9-cholest-7-en-3,11-diol (5), and the 9-H (unnatural) isomers 5,9-cholest-7-en-3,11-diol (7) and 5,9-cholest-7-en-3,11-diol (8). The ring C oxysterols 3, 5, 7, and 8 have been found to be potent inhibitors of HMG-CoA reductase activity in cultured mouse L cells. The similar levels of inhibitory activity indicated that the difference in stereochemistry at C-8 was not a crucial factor for the activity of these oxysterols.