Prostaglandin (PG) endoperoxides (e.g. PGH2) are pivotal intermediates in the biosynthesis of prostaglandins, ubiquitous human hormone-like derivatives of polyunsaturated fatty acids. Although PGs were known to mediate cardiovascular phenomena, it was only recently discovered that the endoperoxides have a direct role in blood chemistry via thromboxane A2 (TXA2) and prostacyclin (PGI2) which are produced from the endoperoxide PGH2. Our successful development of syntheses of the nucleus of PG endoperoxides and studies of its chemical reactions have clearly shown that the chemistry of this strained bicyclic peroxide is unique and cannot be predicted by simple extrapolation of the behavior of any other dialkyl peroxide. Similar work on the novel and reactive bicyclic acetal nucleus of TXA2 is planned as are studies on more complex models as well as on naturally derived PGH2 and TXA2. These model studies led to our important discovery that PGH2 rearranges to new seco prostanoic acid levulinaldehyde products which we named levuglandin E2 (LGE2) and levuglandin D2(LGD2). A total synthesis of the former already developed and one of LGD2 to be developed will make these substances readily available. This will facilitate biological evaluation and allow preparation of radiolabeled derivatives and development of radioimmunoassays which will be used, interalia, to test our hypothesis that levuglandins may explain several reports of unidentified metabolites from arachidonic acid. These include an unidentified non-TXA2 derivative of PGH2 reported to bind to tissue macromolecules and glutahione, and the unidentified metabolites produced in the presence of chick epiphyseal cartilage microsomes or rat renal microsomes. Our exciting new discovery that levuglandins are biologically active in rat uterus encourages us to launch extensive investigations on the biological actions of levuglandins. Since essential fatty acid (EFA) metabolism is very complicated it is important to known all the products and their activities. Studies of the interrelationships and interactions of levuglandins and other EFA metabolites will almost certainly provide new insights into the mechanism and regulation of biological processes, and lead to new therapeutic methods.
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