Leukotrienes, Prostaglandins and Related

2 Leukotrienes. Prostaglandins and Related Compounds.- Examples of the use of the Wittig reaction in the synthesis of compounds related to arachidonic acid include an efficient synthesis of methyl arachidonate (148) by a three-carbon homologation sequence involving (3,3-diisopropoxy-propyl)triphenylphosphorane (149).91 Both diastereomers of trioxilin B3 

Examples of the use of Wittig methods in leukotriene synthesis include the preparation of 13,13-difluoroleukotriene B4 (155)96 and the synthesis of ( + )-LTB4 (159) and homo-LTBa (160) by the reaction of the ylide (156) with the aldehydes (157) and (158), respectively.97 The dihydro-LTBa metabolite (161) and its C-12 epi-analogue have been prepared by a Wittig reaction of the ylide (162) (derived from L-glutamic acid) and the aldehyde 

Examples of standard uses of Wittig reactions to prepare prostaglandin analogues include a synthesis of PGF2a-  

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Initially, the LC-MS analysis of prostaglandins was performed nsing thermospray ionization (Ch. 4.7). Post-colunm methylation of the prostaglandins [42] and conversion into diethyl amino ethyl (DEAE) derivatives [43] was proposed to improve the response. Considerable attention has been paid to the structural characterization of prostaglandins (PG), leukotrienes (LT), and related compounds using ESI-MS-MS, especially by the group of Murphy [ 44-46]. 

Stereospecific syntheses of 5-(5)- and 5-fJU-HETE and transformation to ( ) 5-HPETE R. Zamboni, J. Rokach, Tetrahedron Letters 24, 999 (1983). Review of syntheses J- G. Atkinson, J. Rokach in Handbook of Prostaglandins and Related Lipids The Eicosanoids, A. L, Willis ei at, Eds. (CRC Press, Boca Raton, 19 7), See arachidonic acid and leukotrienes for additional refs. 

Prostaglandins (PGs), leukotrienes (LTs), and related compounds are called eicosanoids,/rom the Greek eikosi ( twenty ). Precursor essential fatty acids containlO carbons and three, four, or five double bonds 8,11,14-eicosatrienoic acid (dihomo-y-linolenic acid), 5,8,11,14-eicosatetraenoic acid (arachidonic acid [AA] Figure 25—1), and 5,8,11,14,17-eicosapentaenoic acid (EPA). AA, the most abundant precursor, is either derived from dietary linoleic acid (9,12-octadecadienoic acid) or ingested directly as a dietary constituent. EPA is a major constituent of oils from fatty fish such as salmon. 

Foegh, M.L. and Ramwell, P.W., The eicosanoids prostaglandins, thromboxanes, leukotrienes and related compounds, in Basic and Clinical Pharmacology, 8th ed., Katzung, B.G., Ed., Lange Medical Books/McGraw-Hill, New York, 2001, chap. 18. 

Prostaglandins Prostaglandins, and the structurally related molecules prostacyclins, thromboxanes and leukotrienes, are called eicosanoids because they contain 20 carbon atoms (Greek eikosi = 20). These hormones are relatively short-lived and hence act locally near to their site of synthesis in the body. They are derived from the common precursor arachidonate (Fig. 2). This polyunsaturated fatty... 

Eicosanoid mediators are derived from araehidonie aeid (eieosatetraenoie) and related poly-unsaturated fatty aeids, sueh as aeid eieosapentanoic acid. These fatty acids are mainly found as constituents of phospholipids in cellular membranes (Figure 12. la), and it is from there that they are mobilized for eicosanoid mediator synthesis. The major classes of eicosanoids are prostaglandins, thromboxanes, and leukotrienes. Eicosanoids are very widespread in the mammalian organism - most cells synthesize them. 

On moist skin or mucous membranes, SO2 is converted to sulfurous acid, a direct irritant. This mechanism accounts for its ability to cause inflammation, burning sensation, and tissue damage (described below) in the eyes, throat, nose, and other respiratory tissues experiencing direct contact. Bronchoconstric-tion and other related effects may be mediated by release of leukotrienes, prostaglandins, or other inflammatory factors. How SO2 causes any of the other systemic and clastogenic effects reported below is unclear. Some evidence suggests that free radicals and oxidative stress may play a role, and that metabolites of SO2 (sulfites) may be responsible for clastogenicity. 

Arachidonic acid ethanolamide (anandamide) and similar compounds are constituents of the brain. Anandamide and certain of the compounds similar with same, bind to the cannabinoid receptor. The binding of the ananamide to the cannabinoid receptor is similar to the binding of A9-tetrahydrocannabinol. There exist in the body many mediators, which are derivatives of arachidonic acid, such as prostaglandins and leukotrienes, which are present as large families of related compounds. Certain of these do not bind to the cannabinoid receptor, and it was one of the aims of the present invention to provide and identify compounds which have pharmacological properties similar to the properties of anandamide. 

Prostaglandins and thromboxanes are eicosanoids that are derived from a common pathway (Figure 19.30), whereas the related leukotrienes are derived from arachidonic acid via a different pathway. 

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