Synthesis of Eicosanoids

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... 

The cerebrovasculature is also an abundant source of eicosanoids. Platelets, leukocytes and vascular endothelium are all capable of synthesizing eicosanoids (see above). Brain microvessels isolated from ischemic rat brain demonstrate enhanced synthesis of eicosanoids, and leukocytes and platelets may account for much of the LTD4 produced during ischemia-reperfusion in the gerbil. 

The synthesis of eicosanoids begins with arachidonic acid (C20 4 n-6 fatty acid) which is component part of cell membranes. The synthetic pathway is outlined in Figure 4.8. A key enzyme in this process is cyclo-oxygenase (COX) which occurs in two... 

Figure 20.3 Essential fatty acids in the diet, production of physiological essential acids and their roles in the cell cycle. Essential fatty adds in the diet are mainly linoleic and a-linolenic but they are converted by desaturation and elongation reactions to the essential acids that are used in phospholipid formation and synthesis of eicosanoids. (For details of the elongation and desaturation reactions and eicosanoid formation, see Chapter 11.).

The cycle makes available essential fatty acids that are required for the phospholipid synthesis necessary for new membrane formation in the proliferating tumour cells (Figure 21.22) and for synthesis of eicosanoids for regulation of proliferation. Such factors are also required by proliferating immune ceUs that may attack tumour cells, so that there will be competition for essential fatty acids between immune and tumour cells. 

Common NSAIDs include aspirin, ibuprofen, indomethacin, naproxen, and ketoprofen. Even though anti-inflammatories generally target cyclooxygenase, there are apparent differences in the details of how they relieve pain. For example, aspirin acts by primarily inhibiting the COX-dependent synthesis of eicosanoids, which are end products of metabolism of essential fatty acids including prostaglandin... 

Resveratrol has also been reported to offer protection against cardiovascular disease, such as coronary heart disease. The effects of resveratrol on factors implicated in the development of coronary heart disease - human platelet aggregation and the synthesis of eicosanoids (lipids) from arachidonate by platelets - were investigated and compared with the actions of other wine phenolics - catechin (1.39), epicatechin (7.18a), and quercetin (1.43) - and the antioxidants a-tocopherol (7.10a), hydroquinone and butylated hydroxytoluene. Resveratrol and quercetin demonstrated a dose-dependent inhibition of platelet aggregation, whereas the other compounds tested were inactive. Resveratrol also inhibited the synthesis of the eicosanoids in a dose-dependent manner, whereas the other phenolics were less effective of not effective at all. Removal of the alcohol from the wine did not diminish the effect on platelet aggregation (Pace-Asciak et al., 1995 Goldberg et al., 1995). 

Saturated fatty acids or unsaturated fatty acids, such as oleic acid (18 1, n-9), can be synthesized by normal mammalian cells that posses elongation and desaturation enzymes (Rosenthal, 1987). However, the polyunsaturated fatty acids of the n-3 and n-6 group, such as linoleic acid (18 2, n-6) or linolenic acid (18 3, n-3), are essential nutrients for animals because they are precursors for the synthesis of eicosanoid hormones such as prostaglandins (Needleman et al., 1986). 

The rate-limiting step in the biosynthesis of eicosanoids is the availabiUty of free precursor, unesterified AA (20 4, o)-6), for both cyclooxygenase (COX) and lipoxygenase en2ymes (13). The initial mobilization cellular AA (20 4, (0-6) is an essential step in the synthesis of eicosanoids (14, 15). Cellular AA is known to be exclusively associated with membrane phospholipids (16-18). It is also tigfrtly regulated through enzymes of the Lands cycle. The enzymes such as phospholipase Aj, arachidonoyl-CoA synthetase and lysophosphatidyl acyltransferases appear to be simultaneously active in order to maintain a steady turnover of AA (20 4, -6) (19). Platelets contain arachidonoyl CoA synthetase (20). 

Kelley, D.S., Taylor, P.C., Nelson, G.J., and Mackey, B.E. 1998a. Arachidonic acid supplementation enhances synthesis of eicosanoids without suppressing immune functions in young healthy men. Lipids 33, 125-130. 

For a phospholipid to move from one side of the bilayer to the other, the polar head must move through the hydrophobic portion of the phospholipid membrane. This process requires a significant amount of energy and is therefore relatively slow. 11. Eicosanoids are derived from arachidonic acid. Medical conditions in which it is advantageous to suppress the synthesis of eicosanoids are anaphylaxis, allergies, pain, the inflammation caused by injury, and fever. 

The eicosanoids are locally active hormones (autocoids) that are derived from precursor polyunsaturated fatty acids. The rate-limiting step in the synthesis of eicosanoids is the phospholipase-regulated release of arachidonic add from membranes. Arachi-donic acid metabolism may follow one of three possible pathways. In the first, the cydooxygenase- peroxidase pathway leads to the formation of the prostenoids - prostaglandins and thromboxanes. In the second, the lipoxygenase pathway yields the leuko-trienes and lipoxins. A third pathway, the cytochrome P-450 mono oxygenase pathway is also involved in the metabolism of arachidonic add. 

Polyunsaturated fatty acids with double bonds three carbons from the methyl end (w3 fatty acids) and six carbons from the methyl end (w6 fatty acids) are required for the synthesis of eicosanoids (see Chapter 35). Because humans cannot synthesize these fatty acids de novo (i.e., from glucose via palmitate), they must be present in the diet or the diet must contain other fatty acids that can be converted to these fatty acids. We obtain w6 and w3 polyunsaturated fatty acids mainly from dietary plant oils that contain the w6 fatty acid linoleic acid (18 2, and the w3 fatty acid a-linolenic acid (18 3, In the body, linoleic acid can be converted by elongation and desatura-... 

Medium-chain triglycerides (MCT) are important components of nutritional supplements used in patients with digestive disorders. They therefore can be employed as an easily absorbed source of calories in patients who have a gastrointestinal (Gl) disorder that may result in malabsorption of nutrients. These diseases include pancreatic insufficiency, intraluminal bile salt deficiency due to cholestatic liver disease, biliary obstruction, ileal disease or resection, and disease causing obstruction of intestinal lymphatics. Remember, however, that MCT do not contain polyunsaturated fatty acids that can be used for synthesis of eicosanoids (see Chapter 35). 

In a simple synthetic example, Jung used AD-mix-P to convert 267 to 268 in quantitative yield and 93% ee, as part of study using dialkyl aminals in asymmetric induction.374 Similarly, Corey used AD-mix-a with 269 as part of synthesis of eicosanoid (11/ , 125)-oxidoarachidonic acid, [,yt the initial diol (270) was not isolated. Internal transesterification led to the hydroxy-lactone 271 in 70% yield and 88% ee. After crystallization, 271 was obtained in 86% yield and 94% ee after crystallization. A comparison of 268 and 271 shows that the different catalysts have produced diols with the opposite absolute configuration. 

Figure 18-1. Synthesis of eicosanoids and sites of inhibitory effects of corticosteroids, nonsteroidal antiinflammatory drugs (NSAIDs), and leukotriene antagonist drugs.

Describe the effects of acetylsalicylate (aspirin) on the synthesis of eicosanoids. 

Synthesis of eicosanoid 555 commenced with a stereoselective organocatalytic cyclopropanation achieved by reacting bromoacetate 559 with Michael acceptor 560 in the presence of dimeric catalyst 561. As the authors were not able to resolve product 562 using an enantioselective HPLC phase, the exact enantiomeric excess could not be determined oti this stage but was found to be satisfactory for the rest of the sequence. With respect to the synthesis of lactonealdehyde 556, the cyclopropanation was carried out by adding the Weinreb- m dt 563 to enone 564 to furnish the key intermediate 565, which was transferred further into 556 in a similar manner (474) (Scheme 118). 

Kumaraswamy G, Padmaja M (2008) Enantioselective Total Synthesis of Eicosanoid and its Congener, Using Organocatalytic Cyclopropanation, and Catalytic Asymmetric Transfer Hydrogenation Reactions as Key Steps. J Org Chem 73 5198... 

Synthesis of eicosanoids from pathogen-derived arachidonic acid ( )... 

Amphibians differ in three important ways from mammals with respect to synthesis of eicosanoids (i) they have EPA as a natural substrate, and thus can potentially produce 3-series prostaglandins and 5 series leukotrienes without dietary supplementation (ii) nucleated erythrocytes and thrombocytes produce cyclooxygenase and lipoxygenase products endogenously and (iii) synthesis of eicosanoids is regulated, at least in part, by environmental temperature. These differences impact the actions of eicosanoids in the cardiovascular system of amphibians. 

The synthesis of eicosanoids from carbohydrates has seen a number of reports this year. Methyl P-2-deoxy-D-ribofuranoside is the starting point for synthesis of 3-hydroxyleukotriene B4 232 and its C3 epimer 233. A double Mitsunobu inversion on the starting material provides the divergence towards the epimeric target. The synthesis utilizes the derived epimeric vinyl stannanes 230 and 231 as a key step. 

---