Aromatic Lipoxin A4 and Lipoxin B4 Analogues Display Potent Biological Activities

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• 作者：Timothy P. O'Sullivan ; Karl S. A. Vallin ; Syed Tasadaque Ali Shah ; J&eacute ; rô ; me Fakhry ; Paola Maderna ; Michael Scannell ; Andre L. F. Sampaio ; Mauro Perretti ; Catherine Godson ; Patrick J. Guiry
• 刊名：Journal of Medicinal Chemistry
• 出版年：2007
• 出版时间：November 29, 2007
• 年：2007
• 卷：50
• 期：24
• 页码：5894 - 5902
• 全文大小：330K
• 年卷期：v.50,no.24(November 29, 2007)
• ISSN：1520-4804

文摘

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 inflammatoryconditions. The native lipoxins LXA₄ and LXB₄ demonstrate potent antiinflammatory and proresolutionbioactions. However, their therapeutic potential is compromised by rapid metabolic inactivation by PGdehydrogenase-mediated oxidation and reduction. Here we report on the stereoselective synthesis of aromaticLXA₄ and LXB₄ analogues by employing Sharpless epoxidation, Pd-mediated Heck coupling, anddiastereoselective reduction as the key transformations. Subsequent biological testing has shown that theseanalogues display potent biological activities. Phagocytic clearance of apoptotic leukocytes plays a criticalrole in the resolution of inflammation. Both LXA₄ analogues (1R)-3a and (1S)-3a were found to stimulatea 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 analoguealso stimulated phagocytosis with a maximum effect observed at 10^-11 M. LX-stimulated phagocytosis wasassociated 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 reducedPMN accumulation.