Platelet activation, prostaglandins

Feverfew is widely consumed in England as a remedy for arthritis and migraine. Feverfew contains parthenolide, which is a member of sesquiterpene. Parthenolide inhibits the activity of prostaglandin synthetase. It also inhibits platelet aggregation and alter serotonin release (Figure 25.2). 

Muitfay M, Rao GH, Robinson P, and Reddy R. (1995). Influx of extracellular calcium and agonist-coupling appear essoitial for the activation of thromboxane AfdepeadeiA phos dK>lipase A human platelets. Prostaglandin Leuk. Essen. Fatty Acids. 53,31-39. 

These differences in the prostaglandins synthesised in endothelium and platelets are important. Intact vascular endothelium does not activate platelets because of the high concentration of prostacyclin in the intima. Subintimal tissues contain little prostacyclin and platelets, under the influence of thromboxane-Aj, immediately adhere and aggregate at any breach in the intima. Atheromatous plaques do not generate prostacyclin—which explains platelet adhesion and thrombosis at these sites. 

Macrophage Nitric oxide Platelet-activating factor Prostaglandins Reactive oxygen species Thromboxane A2... 

Mast cell Adenosine Histamine Leukotrienes Platelet-activating factor Prostaglandin D2 Tryptase... 

Platelet activating factor Prostaglandins Protein kinase C Phospholipase A2 Phospholipase C Polymorphonuclear leukocytes per os (Orally)... 

These data indicate an enhancement of diabetic platelet phospholipase activity whereas prostaglandin synthetase and lipoxygenase activities seem normal. 

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. 

Few areas of organic medicinal chemistry in recent memory have had so many closely spaced pulses of intense research activity as the prostaglandins. Following closely on the heels of the discovery of the classical monocyclic prostaglandins (prostaglandin El, F2, A2, etc.), with their powerful associated activities, for example, oxytocic, blood pressure regulating, and inflammatory, was the discovery of the bicyclic analogues (the thromboxanes, prostacyclin) with their profound effects on hemodynamics and platelet function. More recently, the non-... 

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