Prostaglandins and

PGH2 IS the precursor to a number of prostaglandins and related compounds depending on the enzyme that acts on it One of these cleaves the O—O bond of the endoperox ide and gives PGE2... 

Much of the fundamental work on prostaglandins and related compounds was car ried out by Sune Bergstrom and Bengt Samuelsson of the Karohnska Institute (Sweden) and by Sir John Vane of the Wellcome Foundation (Great Britain) These three shared the Nobel Prize for physiology or medicine m 1982... 

Diarrhea is a common problem that is usually self-limiting and of short duration. Increased accumulations of small intestinal and colonic contents are known to be responsible for producing diarrhea. The former may be caused by increased intestinal secretion which may be enterotoxin-induced, eg, cholera and E. col] or hormone and dmg-induced, eg, caffeine, prostaglandins, and laxatives decreased intestinal absorption because of decreased mucosal surface area, mucosal disease, eg, tropical spme, or osmotic deficiency, eg, disaccharidase or lactase deficiency and rapid transit of contents. An increased accumulation of colonic content may be linked to increased colonic secretion owing to hydroxy fatty acid or bile acids, and exudation, eg, inflammatory bowel disease or amebiasis decreased colonic absorption caused by decreased surface area, mucosal disease, and osmotic factors and rapid transit, eg, irritable bowel syndrome. 

The nomenclature of prostaglandins and prostacyclins is based on the basic prostane skeleton (11), whereas thromboxane (12) is the parent for the thromboxanes. 

The synthetic utihty of the above transformations stems from the fact that many monoesters obtained as a result of hydrolysis may be converted to pharmaceutically important intermediates. For example, the optically active glycerol derivative (27) is a key intermediate in the production of P-blockers. Akyl derivative (25) may be converted into (5)-paraconic acid [4694-66-0] ((5)-5-oxo-3-tetrahydrofurancarboxyhc acid) that is a starting material for the synthesis of (3R)-A-factor. The unsaturated chiral cycHc monoacetate (31) is an optically active synthon for prostaglandins, and the monoester (29) is used for the synthesis of platelet activating factor (PAF) antagonists. 

New Synthetic Routes to Prostaglandins and Thromboxanes, S. M. Roberts and F. Scheinmann Eds. Academic Press London, 1982. 

The necessity for producing large amounts of synthetic prostaglandins and analogs provided the impetus for a number of improvements in the bicyclo[2.2.1]heptene approach. Especially important was the development of an enantioselective modification for the synthesis of chiral prostanoids without resolution (1975) and the invention of a chiral catalyst for the stereocontrolled conversion of 15-keto prostanoids to either 15(5)- or 15(7 )- alcohols. 

Mammals can add additional double bonds to unsaturated fatty acids in their diets. Their ability to make arachidonic acid from linoleic acid is one example (Figure 25.15). This fatty acid is the precursor for prostaglandins and other biologically active derivatives such as leukotrienes. Synthesis involves formation of a linoleoyl ester of CoA from dietary linoleic acid, followed by introduction of a double bond at the 6-position. The triply unsaturated product is then elongated (by malonyl-CoA with a decarboxylation step) to yield a 20-carbon fatty acid with double bonds at the 8-, 11-, and 14-positions. A second desaturation reaction at the 5-position followed by an acyl-CoA synthetase reaction (Chapter 24) liberates the product, a 20-carbon fatty acid with double bonds at the 5-, 8-, IT, and ITpositions. 

There are two isoforms of COX in animals COX-1 (figure a), which carries out normal, physiological production of prostaglandins, and COX-2 (figure b), which is induced by cytokines, mitogens, and endotoxins in inflammatory cells and is responsible for the production of prostaglandins in inflammation. 

Aspirin and other NSAIDs function by blocking the cyclooxygenase (COX) enzymes that carry out the body s synthesis of prostaglandins (Sections 7.11 and 27.4). There are two forms of the enzyme, COX-1, which carries out the normal physiological production of prostaglandins, and COX-2, which mediates the body s response to arthritis and other inflammatory conditions. Unfortunately, both COX-1 and COX-2 enzymes are blocked by aspirin, ibuprofen, and other NSAIDs, thereby shutting down not only tire response to inflammation but also various protective functions, including the control mechanism for production of acid in the stomach. 

Lipid (Section 27.1) A naturally occurring substance isolated from cells and tissues by extraction with a nonpolar solvent. Lipids belong to many different structural classes, including fats, terpenes, prostaglandins, and steroids. 

This method is especially useful as part of a three-component condensation of optically active y-alkoxycyclopentenones leading to prostaglandin and compactin precursors268. 

NSAIDs inhibit cyclooxygenases (COX), the enzymes that catalyze the transformation of arachidonic acid (a ubiquitous cell component generated from phospholipids) to prostaglandins and thromboxanes. Two isoforms, COX-1 and COX-2, are constitutively expressed in peripheral tissues and in the central nervous... 

Anti-cytokines (e.g. IL-1, TNFs, IL-1 receptor constructs) Prostaglandins and PG mimetics... 

Inhibition of inflammatory cytokines (Fig. 2) Humanized monoclonal anti-TNF antibodies (Infliximab (Remicade ), Adalimumab (Humira )) bind with high selectivity to human TNF-a and neutralize its activity. Thereby, infliximab decreases the effects of enhanced TNF levels during inflammatory disease such as production of proteases, chemokines, adhesion molecules, cyclooxygenase products (prostaglandins), and proinflammatory molecules such as interleukin-1 and -6. The antibodies may also recognize membrane-bound TNF-a on lymphocytes and other immune cells. These cells may subsequently become apoptotic or are eliminated via Fc-receptor-mediated phagocytosis. 

Cytotoxics cause an elevation of dopamine levels in the area postrema in animal studies and may release prostaglandins and inhibit enzymes such as enkepha-linases to allow increased levels of enkephalins to activate opioid receptors on dopaminergic nerves. 

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