title: Aromatic lipoxin A4 and lipoxin B4 analogues display potent biological activities.
abstract: Lipoxins are a group of biologically active eicosanoids typically formed by transcellular lipoxygenase activity. Lipoxin A4 (LXA4) and Lipoxin B4 (LXB4) biosynthesis has been detected in a variety of inflammatory conditions. The native lipoxins LXA4 and LXB4 demonstrate potent antiinflammatory and proresolution bioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PG dehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromatic LXA4 and LXB4 analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, and diastereoselective reduction as the key transformations. Subsequent biological testing has shown that these analogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a critical role in the resolution of inflammation. Both LXA4 analogues (1R)-3a and (1S)-3a were found to stimulate a significant increase in phagocytosis of apoptotic polymorphonuclear leukocytes (PMN) by macrophages, with comparable efficacy to the effect of native LXA4, albeit greater potency, while the LXB4 analogue also stimulated phagocytosis with a maximum effect observed at 10-11 M. LX-stimulated phagocytosis was associated with rearrangement of the actin cytoskeleton consistent with that reported for native lipoxins. Using zymosan-induced peritonitis as a murine model of acute inflammation (1R)-3a significantly reduced PMN accumulation.
authors.affiliation: Centre for Synthesis and Chemical Biology, School of Chemistry and Chemical Biology, UCD Conway Institute, University College Dublin, Belfield, Dublin 4, Ireland.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: O'Sullivan
authors.forename: Karl S A
authors.initials: KS
authors.lastname: Vallin
authors.forename: Syed Tasadaque Ali
authors.initials: ST
authors.lastname: Shah
authors.forename: Jérôme
authors.initials: J
authors.lastname: Fakhry
authors.forename: Paola
authors.initials: P
authors.lastname: Maderna
authors.forename: Michael
authors.initials: M
authors.lastname: Scannell
authors.forename: Andre L F
authors.initials: AL
authors.lastname: Sampaio
authors.forename: Mauro
authors.initials: M
authors.lastname: Perretti
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Guiry
mesh_terms: D000199:Actins / Q000502:physiology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis; D002448:Cell Adhesion; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D006801:Humans; D007797:Laminin / Q000502:physiology; D044045:Lipoxins / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D009504:Neutrophils / Q000166:cytology / Q000276:immunology; D010538:Peritonitis / Q000276:immunology; D010587:Phagocytosis; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000199:Actins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D007797:Laminin; D044045:Lipoxins; C040527:lipoxin A4; C042651:lipoxin B4