Revised Manuscript Received September 13, 1995® abstract: Lipoxins (LX) are bioactive eicosanoids that carry a tetraene structure and serve as regulators of inflammation, in part by inhibiting neutrophil migration and adhesion. Lipoxin A4 is rapidly regulated by conversion to inactive LX metabolites via local metabolism that involves dehydrogenation as the predominant route. Here, several LXA4 analogs were designed that resisted rapid conversion by both differentiated HL-60 cellsand recombinant 15-hydroxyprostaglandin dehydrogenase, systems where native LXA4 is degraded within minutes. The rank order of conversion by recombinant dehydrogenase was LXA4 methyl ester> PGE2~ PGE2 methyl ester> LXA4>>> the novel LXA4 analogs. In addition, 15 (RZS)-methyl-LXA4, 15-cyclohexyl-LXA4, and 16-phenoxy-LXA4 proved to retain LXA4 bioactivity and inhibited neutrophil transmigration across polarized epithelial cell monolayers as well as adhesion to vascular endothelial cells. These results indicate that LXA4 analogs can be designed using these criteria to resist rapid transformation and toretain biological actions of native LXA4. Moreover, the results suggest that LXA4 stable analogs can be useful tools both in vitro and in vivo to evaluate LXA4 actions and therapeutic potential.

Eicosanoids play important roles in regulating essential multicellular processes including inflammation, thrombosis, and tissue repair. Lipoxins (LX) are a specific series of eicosanoids whose members carry a conjugated tetraene stmcture (Samuelsson et al., 1987). They are generated by unique pathway assemblies that can involve cell—cell interactions and/or transcellular biosynthetic routes, and