Journal of Chemistry and Biochemistry

Chemical Synthesis of Ring C oxygenated Derivatives of Cholesterol and their Inhibition of Sterol Biosynthesis
Nida A McKee, Chi Luo, Don E Parish, Frederick R Taylor, Edward J Parish

Abstract
Chemical synthesis of oxygenated derivatives of cholesterol and lanosterol, have been shown to produce oxysterols with significant activity as inhibitors of 3-hydroxy-3- methylglutaryl (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 3- benzoyloxy-9,11-epoxy-5-cholest-7-ene (1), whose structure has been confirmed by X-ray crystallographic analysis. Chemical modification of 1 produced 9,11- epoxy-5-cholest-7-en-3-ol (2), the 9-H (natural) isomers 5,9-cholest-7-en- 3,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.

Full Text: PDF     DOI: 10.15640/jcb.v3n2a1