Eicosanoids

Eicosanoids are unsaturated C20 acids. They are aliphatic (leucotrienes) or contain either a five-membered carbocyclic ring (prostaglandins, prostacyclins) or a six membered 0-heterocyclic ring (thromboxanes). Hydroxy, keto, and epoxy groups may be present. 

Eicosanoids are produced in higher animals. Prostaglandins have also been found in invertebrates, e.g., the coral Plexaura homomalla which contains 1.3 % 15-epiprostaglandin Eg, and in plants. 

1 Lipoxygenase 2 prostaglandin cyclooxygenase 3 reductase 4 prostaglandin synthase 5 thromboxane synthase 6 prostacyclin synthase 

Eicosanoids possess hormone activity in higher animals (E 3.1). Most important is the influence of prostaglandins and leucotrienes on inflammation and of prostaglandins and thromboxanes on blood platelet aggregation. 

Platelet homeostasis is maintained by a delicate balance in the transformation of endoperoxide II to thromboxane Ag (reducing the intraplatelet cAMP level which is followed by aggregation) and to prostacyclin (doing the reverse). Prostacyclin biosynthesis takes place in the endothelial cells of arteries, whereas the thromboxanes are synthesized in the collagen. Thus collagen-stimulated platelet aggregation takes place only at points of endothelial damage. 

Preformed eicosanoids are not stored within cells for secretion. Eicosanoids are synthesized and released extremely rapidly in response to a stimulus to the cell. They have very short half lives in the body, and it is now widely believed that these are locally acting agents with a very restricted 

The involatility and thermal lability of eicosanoids render them appropriate candidates for FABMS, and this technique has been used to compare directly underivatized leukotriene C4 (38) a slow-reacting substance of anaphylaxis, from biological and synthetic origin 104). In the negative ion FAB spectrum, prominent [M —H] and [M —2H + Na] ions were observed at m/z 624 and 646 respectively and diagnostic fragment ions at m/z 306 and 319 as indicated. 

Prior to the demonstration of AA metabolism by P450, several groups demonstrated the role of microsomal P450s in the o /a)-l hydroxylation of prostanoids - and, more recently, leukotrienes- . Most of these reactions are considered to be involved in eicosanoid catabolism and excretion, but their potential relevance in eicosanoid bioactivation or inactivation, and/or in the control of organ/cell eicosanoid levels has only begun to be explored. We will first discuss the role of P450 in the metabolism of eicosanoids, and then concentrate on the studies of its role in AA metabolism and bioactivation. 

Q acids respectively. Iso-acids have an even number of carbon atoms, anteiso-acids have an odd number. The two unsaturated anteiso-compounds are part of the sex pheromone of some Trogoderma species 

Prostacyclin is produced in vascular endothelium and plays a role in the regulation of blood flow. It elicits vasodilation and prevents aggregation of platelets (functional antagonist of thromboxane). 

Thromboxane A2 is a local hormone of platelets it promotes their aggregation. Small defects in the vascular or capillary wall elicit the formation of thromboxane. 

Leukotrienes2 are produced mainly in leukocytes and mast cells. Newly formed leukotrienes can bind to glutathione. From this complex, glutamine and glycine can be cleaved, resulting in a larger number of local hormones. Leukotrienes are pro-inflammatory they stimulate invasion of leukocytes and enhance their activity. In anaphylactic reactions, they produce vasodilation, increase vascular permeability, and cause vasoconstriction. 

Efforts to synthesize stable derivatives of prostaglandins for therapeutic applications have not been very successful to date. Dino-prostone (PGE2), carboprost (15-methyl-PGF2a) and mifeprostone are uterine stimulants (p.130, 254). Misoprostol is meant to afford protection of the gastric mucosa but has pronounced systemic side effects. All these substances lack organ specificity. 

1 Name derived from Greek eikosi = twenty for triene (tri=three), although leukotrienes possess 

All naturally occurring prostaglandins are derived through the cyclization of 20-carbon unsaturated fatty acids such as arachidonic acid, which in turn is synthesized from the essential fatty acid linoleic acid. The prostaglandins are named according to their ring substitutions and the number of additional side-chain double bands, as seen in prostaglandins E1( Fla, and F2a. 

In addition to serving as a precursor for the synthesis of prostaglandins, arachidonic acid is also a precursor for the synthesis of prostacyclin, thromboxanes, and leukotrienes. 

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Older versions of the lUPAC rules called the unbranched carboxylic acid with 20 car bon atoms e/cosano/c aad Consequently icosanoids are often referred to as eicosanoids... 

Allergic Seasonal or Perennial Rhinoconjunctivitis. Histamine can cause all pathologic features of allergic rhinitis (35—37), with the exception of late-phase inflammatory reactions. Pmritus is caused by stimulation of receptors on sensory nerve endings prostaglandins (qv) may also contribute. Sneering, like pmritus, is an H -mediated neural reflex and can also be mediated by eicosanoids. Mucosal edema, which manifests as nasal... 

CP 55940 (79) and nabilone (80) are synthetic ligands for the cannabiaoid receptor. However, the identification of the eicosanoid, anandamide (81), as an endogenous cannabimimetic has provided an important tool to study cannabiaoid receptor function. 

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

Leukotrienes. Leukotrienes, products of the Hpoxygenase pathway, are generally less radioprotective than the PGs, with the exception of LTC4, which is among the most potent of the naturally occurring eicosanoids (214). LTC radioprotects V79 hamster cells in vitro and mouse CEU-S and... 

Among vertebrate species, the neuro-endocrine-immime system is responsible for many complex, inter-related physiological processes including neuronal, homeostatic, reproductive and immune functions. There are four main types of hormone polypeptides, eicosanoids, steroids and thyroid hormones. Reflecting the inter-dependency of the neiiro-endocrine and immune systems, hormones, neuropeptides and other neiirotransmitters are known to be produced by some immune cells and play a role in the regulation of the immune system, while endocrine and nervous tissues express receptors for many substances produced by the immune system. The major focus of interest in endocrine disruption has... 

The organization of Part Two is according to structural type. The first section, Chapter Seven, is concerned with the synthesis of macrocyclic compounds. Syntheses of a number of heterocyclic target structures appear in Chapter Eight. Sesquiterpenoids and polycyclic higher isoprenoids are dealt with in Chapters Nine and Ten, respectively. The remainder of Part Two describes syntheses of prostanoids (Chapter Eleven) and biologically active acyclic polyenes including leukotrienes and other eicosanoids (Chapter Twelve). 

A similar result was obtained with substrates having the full eicosanoid side chain and a 12,13(Z)-double bond regardless of whether the 14,15-double bond is or Z (Ref. 3). 

Hybridalactone, a novel marine derived eicosanoid from Laurencia hybrida, appears to be biosynthesized by a unique pathway from eicosapentaenoic acid. The synthesis of hybridalactone was carried out enantiospecifically from (+)-bicyclo[3.2.0]hept-4-ene-l-one so as to provide proof of stereochemistry (Ref. 4). 

The first step in the biosynthesis of eicosanoids from arachidonic acid is generally a lipoxygenation reaction. The resulting hydroperoxides (HPETE s) can undergo reduction to the corresponding alcohols (HETE s). Preparative routes to the 5-, 11-, and 15-HETE s and HPETE s have been developed as oudine below. 

Some fatty acids are not synthesized by mammals and yet are necessary for normal growth and life. These essential fatty aeids include llnoleic and y-linolenic acids. These must be obtained by mammals in their diet (specifically from plant sources). Arachidonic acid, which is not found in plants, can only be synthesized by mammals from linoleic acid. At least one function of the essential fatty acids is to serve as a precursor for the synthesis of eicosanoids, such as... 

We turn now to the biosynthesis of lipid structures. We begin with a discussion of the biosynthesis of fatty acids, stressing the basic pathways, additional means of elongation, mechanisms for the introduction of double bonds, and regulation of fatty acid synthesis. Sections then follow on the biosynthesis of glyc-erophospholipids, sphingolipids, eicosanoids, and cholesterol. The transport of lipids through the body in lipoprotein complexes is described, and the chapter closes with discussions of the biosynthesis of bile salts and steroid hormones. 

Eicosanoids, so named because they are all derived from 20-carbon fatty acids, are ubiquitous breakdown products of phospholipids. In response to appropriate stimuli, cells activate the breakdown of selected phospholipids (Figure 25.27). Phospholipase Ag (Chapter 8) selectively cleaves fatty acids from the C-2 position of phospholipids. Often these are unsaturated fatty acids, among which is arachidonic acid. Arachidonic acid may also be released from phospholipids by the combined actions of phospholipase C (which yields diacyl-glycerols) and diacylglycerol lipase (which releases fatty acids). 

A Variety of Stimuli Trigger Arachidonate Release and Eicosanoid Synthesis... 

The release of arachidonate and the synthesis or interconversion of eicosanoids can be initiated by a variety of stimuli, including histamine, hormones such as epinephrine and bradykinin, proteases such as thrombin, and even serum albumin. An important mechanism of arachidonate release and eicosanoid syn-... 

Compounds 111 having structural features of the dual cyclooxygenase (COX)/5-lipooxygenase (5-LO) inhibitor tepoxalin and the 5-LO inhibitor ABT-761 were prepared. Many of these hybrid compounds are potent COX and 5-LO inhibitors two compounds (111, r =McO, R = R" = R = H, R = NH2, R = Me and r = MeO, R = R = Me, R" = R = H, R = Cl) inhibited eicosanoid biosynthesis in an ex vivo assay, but neither improved on the main deficiency of tepoxalin, duration of 5-LO inhibitory activity (99BMCL979). Compounds 111 inhibit the production of arachidonic acid products associated with 5-lipoxygenase and cyclooxygenase and are useful in the treatment of inflammatory disorders (99USP5925769). 

Epoxide ring-opening witli transfer of an sp carbon moiety was applied in a sbori syntliesis [44] of eicosanoid 56 [45], relevant in marine prostanoid biosyn-tliesis (Scheme 9.13). Honioallyl alcohol 55 was obtained in good yield from 54 by use of a cyano-G dman alketiylciiprate [46]. 

Lipids are naturally occurring organic molecules that have limited solubility in water and can be isolated from organisms by extraction with nonpolar organic solvents. Fats, oils, waxes, many vitamins and hormones, and most nonprotein cell-meznbrane components are examples. Note that this definition differs from the sort used for carbohydrates and proteins in that lipids are defined by a physical property (solubility) rather than by structure. Of the many kinds of lipids, we ll be concerned in this chapter only with a few triacvlglycerols, eicosanoids, terpenoids, and steroids. 

Prostaglandins, together with related compounds called thromboxanes and leukotrienes, make up a class of compounds called eicosanoids because they are derived biologically7 from 5,8,11,14-eicosatetraenoic acid, or arachidonic... 

Figure 27.3 Structures of some representative eicosanoids. All are derived biologically from arachidonic acid.

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