Synthesis of two polyunsaturated natural products using epa as starting material

With the advent of drug design, high throughput screening and combinatorial chemistry, medicinal chemists became less and less interested in natural products as a source for drugs. In the last two decades, medicinal chemists seemed inclined towards the ap parently more accessible synthetic products obtained from combinatorial chemistry. However, it has been recognized that combinatorial chemistry has severe limitations in generating novel classes of biologically active compounds, as seen by the sharp decli ne of number of approved drugs the last ten years. In this research proposal we will prepare two polyunsaturated marine natural products, bacillariolide I and zonariaenon, from eicosapentaenoic acid. These two natural products, as well as some of the in termediates, will be submitted to molecular modeling and biological testing as potential antagonists or agonists for the peroxisome proliferating activating delta receptor. The ethyl ester of eicosapentaenoic is produced in Sandefjord, Norway by the Norw egian pharmaceutical company Pronova. Pronova is establishing a synthetic group in Oslo. In the near future Pronova must need synthetic chemists with competence and a strong background in handling air and light sensitive polyunsaturated fatty acids, as w ell as their derivatives. This project will gain knowledge in how to handle and use eicosapentaenoic acid as a starting material in organic synthesis. Moreover, the natural products prepared in this research proposal may aid the elucidation of the physio logical role of the peroxisome proliferator-activated receptors. With full knowledge of these receptors and their physiological role, control of a number of maladies, such as type 2 diabetes, obesity and cardiovascular disease may be possible.