Synthesis and Anti-inflammatory and Pro-resolving Activities of 22- OH-PD1, a Monohydroxylated Metabolite of Protectin D1

ABSTRACT: Protectin D1 (PD1 (3)), a C22-dihydroxylated polyunsaturated fatty acid biosynthesized from all-Z-docosahexaenoic acid, belongs to the new family of endogenous mediators referred to as specialized pro-resolving lipid mediators. PD1 (3) is a natural product that displays potent anti-inflammatory properties together with pro-resolving actions including inhibition of polymorphonuclear leukocyte (PMN) infiltration and promotion of macrophage phagocytosis and efferocytosis. Given its potent endogenous actions, this compound has entered several clinical development programs. Little has been reported on the metabolism of PD1 (3). The synthesis and biological evaluations of the ω-22 monohydroxylated metabolite of PD1 (3), named herein 22-OH-PD1 (6), are presented. LC-MS/MS data of the free acid 6, obtained from hydrolysis of the synthetic methyl ester 7, matched data for the endogenously produced 22-OH-PD1 (6). Compound 6 exhibited potent pro-resolving actions by inhibiting PMN chemotaxis in vivo and in vitro comparable to its precursor PD1 (3) and decreased pro-inflammatory mediator levels in inflammatory exudates. The results reported herein provide new knowledge of the metabolism of the protectin class of specialized pro-resolving mediators. Several naturally occurring chemical mediators have beenidentified that have the capacity to initiate, modulate, and reduce acute inflammation as well as stimulate resolution.1,2 Recent efforts have established that the return to homeostasis, i.e., catabasis,3 is mediated by active biosynthesis an