MBRS undergraduate and graduate students will develop a variety of synthetic organic and analytical chemistry skills by participating in ongoing research directed toward the development of chemicals for reducing blood serum cholesterol levels as a means of controlling atherosclerosis. The goal of this research experience is for the ethnic minority participants to learn about the nature and importance of synthetic organic chemistry as it is applied in solving biomedical problems in hope of influencing the participants to choose biomedical research as a career. A research experience will be available in three areas: 1) synthesis of chemicals that may aid in development of drugs which directly block the biosynthesis of excess sterols in tissues; 2) synthesis of chemicals that appear in the natural cascade by which sterol biosynthesis is regulated, or that are useful in delineating that cascade; and 3) synthesis of chemicals that may be able to block the absorption of cholesterol from the intestine or that may be useful in defining how certain dietary sterols are able to exercise such an effect. The first of these specific aims will be approached by synthesis of compounds that are close analogues of HMG-CoA, the substrate for the enzyme HMG-CoA reductase, the key regulated enzyme in sterol biosynthesis. However, these compounds cannot be reduced but to a close analogue of the enzyme-bound intermediate in the two step reduction. An important feature of this research is to be determination of the stereochemistry of a labile hemithioacetal in the intermediate. The second specific aim will be achieved by synthesis of omega-oxidized derivatives of farnesoic and geranoic aid which are thought to be non-sterol regulators of HMG-CoA reductase. Other compounds to be synthesized as part of the search for the natural regulatory cascade are sterol-24,25-epoxides and their derivatives and presterol epoxides such as squalene- 2,3:22,23-bisepoxide. Two classes of compounds will be synthesized as regulators for cholesterol absorption. A series of carbon 24 alkylated and dialkylated cholesterols will be prepared to be used in learning how certain plant and shellfish sterols are able to inhibit cholesterol absorption. Potential inhibitors of cholesterol esterase, which will catalyzes the essential hydrolysis of intestinal cholesterol esters, will also be prepared.
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