Lipoxins A and

A class of 5,6,15- and 5,14,15-trioxygenated metabolites of arachidonate has been described by Samuelsson et al. Two of these compounds, termed lipoxins A and B, have recently been assigned the structures shown below. 1 Outlined below is a synthesis of a putative biosynthetic precursor of these compounds. Syntheses of the structures assigned to lipoxins A and B have also been accomplished.3.4... 

Schreiber s model has also proved to be a general approach to a series of oxygenated metabolites of arachidonic acid, such as lipoxin A and lipoxin B.50 The family of linear oxygenated metabolites of arachidonic acid has been implicated in immediate hypersensitivity reactions, inflammation, and a number of other health problems. Among these metabolites, several compounds, such as lipoxin A, lipoxin B, 5,6-diHETE, and 14,15-diHETE possess 1-substituted (/ )-1 -alken-3.4-diol 84 as a common substructural moiety. Therefore, the car-binol 83 is an ideal substrate for generating compound 84 by applying Sharpless epoxidation reaction.50... 

Lipoxins have diverse effects on leukocytes, including activation of monocytes and macrophages and inhibition of neutrophil, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin inhibit natural killer cell cytotoxicity. 

S)-HETE is a potent chemoattractant for smooth muscle cells, causing migration at concentrations as low as 1 fmol/L it may play a role in myointimal proliferation that occurs after vascular injury such as that caused by angioplasty. Its stereoisomer, 12(K)-HETE, is not a chemoattractant but is a potent inhibitor of the Na+/K+ ATPase in the cornea. LTC4 and LTD4 reduce myocardial contractility and coronary blood flow, leading to cardiac depression. Lipoxin A and lipoxin B seem to exert coronary vasoconstrictor effects. 

Nicolaou have now carried out some interesting synthetic work which confirms the stereostructures shown in formulae (183) and (l84) for lipoxin A and lipoxin B respectively. 

Sodin-Semrl, S, Spagholo, A, Mikus, R, Barbaro, B, Varga, J and Fiore, S (2004) Opposing regulation of interleukin-8 and NF-kB responses by lipoxin A and serum amyloid A via the common lipoxin A receptor. Int J Immunopathol Pharmacol, 17(2), 145-156. 

Hansson A, Serhan CN, Haeggstrom J, Ingelman-Sundberg M, Samuelsson B. Activation of protein kinase C by lipoxin A and other eicosanoids. Intracellular action of oxygenation products of arachi-donic acid. Biochem Biophys Res Commun 1986 134 1215-1222. 

Rats fed a purified nonlipid diet containing vitamins A and D exhibit a reduced growth rate and reproductive deficiency which may be cured by the addition of linoleic, a-linolenic, and arachidonic acids to the diet. These fatty acids are found in high concentrations in vegetable oils (Table 14-2) and in small amounts in animal carcasses. These essential fatty acids are required for prostaglandin, thromboxane, leukotriene, and lipoxin formation (see below), and they also have various other functions which are less well defined. Essential fatty acids are found in the stmctural lipids of the cell, often in the 2 position of phospholipids, and are concerned with the structural integrity of the mitochondrial membrane. 

Wong, A., Hwang, S.M., Kreft, A. and Marshall, L. (1991) Presented at the Xlth Washington International Spring Symposium (Prostaglandins, Leukotrienes, Lipoxins and PAF), Washington DC Abstr. 307. 

Fig. 7.2 Chemical structures of lipoxins, resolvins and neuroprotectins. Lipoxin A4 (a), Lipoxin B4 (b) 16,17S-docosatriene (c) 10,17S-docosatriene (d) 7,16,17S-resolvin (e) and 4S5,17S-resolvin (f). These metabolites retard the actions of arachidonic acid and its metabolites...

Machado F. S., Johndrow J. E., Esper L., Dias A., Bafica A., Serhan C. N., and Aliberti J. (2006). Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nature Med. 12 330-334. 

The EFA stored in the phospholipids of cell membranes are released by phospholipases, and then undergo oxidative transformation by the cyclooxygenase (COX) pathway to prostanoids and by the lipoxygenase pathway to hydroxy fatty acids and leukotrienes. The metabolism to prostanoids is catalyzed by two isoenzymes of COX, a constitutive (COX-1) and an inducible form (COX-2). The main products of COX metabolism of AA are prostaglandin E2 (PGE2), PGI A, and PGD2. In addition, A A is converted via 15-lipoxygenase to 15-hydroxyeicosatetraenoic acid (15-HETE) and lipoxins, by... 

AA, EPA, DHA, GLA, DGLA, LXs and resolvins suppress lL-1, lL-2, lL-6, and TNF-a prodnction by T cells (110-112, 149, 176-180). This claim suggests that EFAs/PUFAs and their metabolites function as endogenous anti-inflammatory molecules and regulate immune response and thus are likely to be of benefit in obesity, insulin resistance, atherosclerosis, metabolic syndrome X, type 2 diabetes mellitus, CHD, depression, and Alzheimer s disease that are considered as diseases of low-grade systemic inflammation (1-8, 24, 120). Some beneficial actions of PUFAs in various inflammatory conditions are because of the formation of anti-inflammatory compounds such as lipoxins, resolvins, and neuroprotectin Dl. 

Fig. 1 Proposed homeostatic regulation of inflammation in effective host defence. The initial phase of inflammation is initiated by a host of pro-inflammatory cytokines and eicosanoids which subsequently become diminished with time, and are coupled with the likely activation of anti-inflammatory and pro-resolution mediators, including the lipoxins, resolvins and protectins. Typically, IL 13 up-regulates 15-LO gene expression of human blood monocytes for example (Nassar et al. 1994). The associated increase in enzyme activity results in an increase in LX generation which promotes the resolution phase of inflammation. IL, interleukin TNF-a, tumour necrosis factor-a MCP-1, monocyte chemotactic protein-1 RANTES, regulated upon activation, normal T-cell expressed and secreted TGF i, transforming growth factor...

Chiang N, Fierro IM, Gronert K, Serhan CN (2000) Activation of lipoxin A(4) receptors by aspirin-triggered lipoxins and select peptides evokes Ugand-specific responses in inflammation. J Exp Med 191 1197— 1208... 

Goh J, Baird AW, O Keane C, Watson RW, Cottell D, Bernasconi G, Petasis NA, Godson C, Brady HR, MacMathuna P (2001) Lipoxin A(4) and aspirin-triggered 15-epi-lipoxin A(4) antagonize TNF-alpha-stimulated neutrophil-enterocyte interactions in vitro and attenuate TNF-alpha-induced chemokine release and colonocyte apoptosis in human intestinal mucosa ex vivo. J Immunol 167 2772-2780... 

Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN (2001) Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. Am J Pathol 158 3-9... 

Levy BD, De Sanctis GT, Devchand PR, Kim E, Ackerman K, Schmidt BA, Szczeklik W, Drazen JM, Serhan CN (2002) Multi-pronged inhibition of airway hyper-responsiveness and inflammation by lipoxin A(4). Nat Med 8 1018-1023... 

Madema P, Godson C, Hannify G, Murphy M, Brady HR (2000) Influence of lipoxin A(4) and other Upoxygenase-derived eicosanoids on tissue factor expression. Am J Physiol Cell Physiol 279 C945-953... 

Papayianni A, Serhan CN, Brady HR (1996) Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. J Immunol 156 2264—22672... 

Wu SH, Lu C, Dong L, Zhou GP, He ZG, Chen ZQ (2005) Lipoxin A inhibits TNF-alpha-induced production of interleukins and proliferation of rat mesangial cells. Kidney Int 68 35 6... 

Nokami, J., Furukawa, A., Okuda, Y, Hazato, A., and Kurozumi. S., Palladium-catalyzed coupling reactions of bromobenzaldehydes with 3,4-di(tert-butylmethylsilyloxy)-l-alkene to (3,4-dihydroxy-alkenyl)benzaldehydes in the synthesis of lipoxin analogues, Tetrahedron Lett., 39, 1005, 1998. Adiyaman, M., Lawson, J.A., FitzGerald. G.A., and Rokach, J.. Synthesis and identification of the most abundant urinary type VI isoprostanes, Tetrahedron Lett., 39, 7039, 1998. 

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