Prostacyclin-Derived Products

The anions of the HWE reagents 27a,b were reacted with the chiral monoketone 99 to afford the corresponding Z- and -olefins 100 and 101 with high diastereo-meric excesses, depending upon which enantiomer of the chiral phosphonate was employed. The olefinic products thus obtained served as key intermediates in the synthesis of prostacyclin derivatives [59, 60]. A closely related chiral reagent, 24, bearing 8-phenylnormenthol [67], both enantiomeric forms of which are readily accessible, provided an improved diastereoselectivity in favor of the -isomer 101 (Scheme 7.16). 

The enzyme system responsible for the biosynthesis of PGs is widely distributed in mammalian tissues and has been extensively studied (2). It is referred to as prostaglandin H synthase (PGHS) and exhibits both cyclooxygenase and peroxidase activity. In addition to the classical PGs two other prostanoid products, thromboxane [57576-52-0] (TxA ) (3) and prostacyclin [35121 -78-9] (PGI2) (4) are also derived from the action of the enzyme system on arachidonic acid (Fig. 1). 

A thrombotic tendency is present in diabetes due to an imbalance between prostacyclin and thromboxane. Lipid peroxides and newly generated free radicals are thought to inhibit the vasodilator and anti-platelet effects of endothelial-derived prostacyclin, but stimulate platelet cyclooxygenase activity, thereby promoting the production of thromboxane A2. This leads to vasoconstriction and platelet aggregation - the concept of peroxide vascular tone (Halliwell and Gutteridge, 1989). 

Prostacyclin, a potent inhibitor of platelet aggregation, is derived from metabo-lisation of arachidonic acid by endothelial cells, and shear stress increases its production rate [12]. It is postulated that this effect is due to perturbations of the permeability of the plasma membrane changing the cytosolic Ca + content and leading to an increase in phospholipase C activity (through the by-passing of the receptor requirement), which contributes to a higher production of arachidonic metabolites. 

Jia et al. (2001) have identified a 12-amino-acid synthetic peptide derived from exon 6 (based on sequence of VEGF189) that inhibits VEGF binding to HUVECs and porcine aortic ECs. It also inhibits VEGF-stimulated ERK activation and prostacyclin production. The peptide blocks the interaction of VEGF with KDR and neuropilin-1. 

Figure 16.24 Major prostaglandin and leukotriene products derived from arachidonic acid via the cyclooxygenase and 5-lipooxygenase pathways. Major enzymes 1, cyclooxygenase 2, hydroperoxidase 1 + 2, prostaglandin endoperoxidase synthetase 3, thromboxane synthetase 4, prostacyclin synthetase 5, 5-lipooxygenase 6, 9-ketoisomerase 7, PGH-PGF2a reductase 8, 11-ketoisomerase 9, PGE reductase 10, PGD reductase. (Reproduced by permission from Nelson NA, Kelly RC, Johnson, RA. Prostaglandins and the arachidonic acid cascade. Chem Eng News August 30-44, 1982.)...

Prostacyclin (8, 256-257). The Upjohn synthesis of prostacyclin has been described in detail. The key step, iodination of prostaglandin F2. methyl ester, is greatly improved by use of I2 and KI rather than I2 alone. The paper also reports synthesis of the related prostaglandin Ii (5,6-dihydroprostacyclin), prostaglandin I3 (derived from prostaglandin p3 ), and 6-ketoprostaglandin Fi , the hydrolysis product of prostacyclin. ... 

Enzymic lipid peroxidation reactions are a common reaction in mammalian cells as response to stress from outside. In contrast to plants mammalian cell membranes contain arachidonic acid instead of linolenic acid. The latter is known to generate by LPO processes physiological potent compounds prostaglandines, prostacyclines, thromboxanes and leukotiienes [221]. In addition a great number of other LPO products derived not only from arachidonic acid but also from linoleic acid have been detected in blood, especially low density lipoprotein (LDL) and tissue samples of humans [222-227]. These are increased especially in diseases combined with cell degradation [228], indicating that cell death in plant and mammalian cells is connected with a similar cascade of events. 

Cardiovascular effects of prostaglandins are more complex. The coagulation system is clearly modulated by platelet-derived thromboxanes, which have procoagulation effects and the anticoagulative effects of endothelial cell-derived prostacyclin. Thromboxanes are clearly COX-1 derived because platelets do not express COX-2. The source of endothelial cell prostacyclin production is less clear with both enzymes expressed and mixed opinions on the relative contribution of the two enzymes. Recent results with Vioxx, a selective COX-2 inhibitor, imply a modest effect on myocardial infarction rate in patients taking the compound but do not define whether this is caused by a change in ratio simply by a lack of platelet effect or that inhibition of endothelial cell prostacyclin also skews the pro- and anticoagulant ratio. 

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