Lipoxins and Related Eicosanoids: Biosynthesis,Biological Properties,and Chemical Synthesis

Among the various enzymes found in human tissues that act on arachidonic acid, there are three major types of lipoxygenases (LO), operating at the 5-, 12-, and 15-positions. The 5-LO is a key enzyme and plays a central role in the biosynthesis of leukotrienes, which are potent arachidonate-derived mediators of allergy and inflammation. Because of the importance of the 5-LO-derived products in human pathophysiology, studies were initiated to examine the consequences of initial lipoxygenation at C15 of arachidonic acid as well as to probe interactions between the major LO pathways. These studies led to the identification of a new series of biologically active tetraene-containing eicosanoids termed lipoxins. This article summarizes the isolation, biosynthesis, and chemical synthesis of lipoxins and related systems, and reviews recent results concerning their formation and biological activities. The total synthesis of these molecules based on a new and general synthetic strategy involving palladium catalysis is reviewed. This synthetic approach has allowed the preparation of several types of acyclic eicosanoids in their naturally occurring forms which, in turn, allowed comparisons with naturally derived materials and enabled detailed studies of the biological actions of these biomolecules. Structure–activity relationships were also derived by combining chemical synthesis and biological investigations.