Prostaglandins and Thromboxanes

thromboxane 82 (177) was first converted into the 1,15-macrolide (178) which, after dehydration to (179), was elaborated into the bromohydrin (I80). A modified Mitsunobu reaction with (180) next produced the 10-bromothromboxane A2 derivative (I8la) 

The lipoxins are a series of newly discovered, biologically active compounds formed from arachidonic acid in human leukocytes. 

Owing to their biological importance and doubts concerning their 

Nicolaou have now carried out some interesting synthetic work which confirms the stereostructures shown in formulae (183) and (l84) for lipoxin A and lipoxin B respectively. 

---

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

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... 

Figure 23-6. Conversion of arachidonicacid to prostaglandins and thromboxanes of series 2. (PG, prostaglandin TX, thromboxane PGI, prostacyclin HHT, hydroxyheptadecatrienoate.) (Asterisk Both of these starred activities are attributed to one enzyme prostaglandin H synthase. Similar conversions occur in prostaglandins and thromboxanes of series 1 and 3.)...

Lelcuk, S., Alexander, F., Kobzik, L., Valeri, C.R., Shepro, D. and Hechtman, H.B. (1985). Prostaglandins and thromboxane A2 moderate post-ischaemic renal failure. Surgery 98, 207-212. 

Cyclooxygenase Inhibitors. The synthesis of prostaglandin and thromboxane has been linked with multiple organ failure in animals and humans with sepsis. Bernard et al. (B18) reported the results of a large trial of the cyclooxygenase inhibitor ibuprofen in patients with sepsis. Treatment for 48 hours with... 

As the first isolable intermediate in the bioconversion of arachidonic acid into prostaglandins and thromboxanes (Eq. 3), PGG2 is a bicyclic peroxide of immense biological importance. It is difficult to obtain pure from natural sources and the presence of the 15-hydroperoxide group adds a further dimension of chemical lability to that associated with the 9,11-peroxide bridge. The chemical synthesis of PGG2 is thus a landmark in prostaglandin chemistry. It also represents a pinnacle of success for the silver-salt route to bicyclic peroxides. 

Eicosanoid synthesis. Arachidonic acid is converted by cyclooxygenases into prostaglandins, and thromboxanes. Lipoxygenases convert arachidonic acid into HPETEs, which are then converted to lipoxins, leukotrienes, and 12-HETE (hydroxyeicosatetraenoic acid). Epoxygenases convert arachidonic acid into epoxides. 

Figure 1.9. Overview of the biosynthesis of ecosanoids. The 20 carbon fatty acid arachidonic acid is released from cell membrane phospholipids by the actions of phospholipase A2. Free arachidonic acid forms the precursor of prostaglandins and thromboxanes via the multi-enz5une cyclooxygenase pathway, while leukotrienes are formed via the lipoxygenase pathway...

Smdies of the stmcture-activity correlations and synthetic modifications of prostaglandins and thromboxane are extremely active fields. Although a large number of analogs have been synthesized, pharmacological information on these analogs is still unfolding. 

B. Samuelsson, P. W. RamweU, R. Paoletti (1976). Advances in Prostaglandin and Thromboxane Research, 18 vols. New York Raven Press. 

The NSAIDs (eg, indomethacin, ibuprofen see Chapter 36) block both prostaglandin and thromboxane formation by reversibly inhibiting COX activity. The traditional NSAIDs are not selective for COX-1 or COX-2. Selective COX-2 inhibitors, which were developed more recently, vary—as do the older drugs—in their degree of selectivity. Indeed, there is considerable variability between (and within) individuals in the selectivity attained by the same dose of the same NSAID. Aspirin is an irreversible COX inhibitor. In platelets, which are anuclear, COX-1 (the only isoform expressed in mature platelets) cannot be restored via protein biosynthesis, resulting in extended inhibition ofTXA2 biosynthesis. 

Malonaldehyde is found in human and animal tissue as an end-product of lipid peroxidation. It is also a side-product of prostaglandin and thromboxane biosynthesis. Malonaldehyde is present in blood platelets and in serum (lARC, 1985). 

The thromboxanes have a six-membered ring containing an ether. They are produced by platelets (also called thrombocytes) and act in the formation of blood clots and the reduction of blood flow to the site of a clot. The nonsteroidal antiinflammatory drugs (NSAIDs)— aspirin, ibuprofen, and meclofenamate, for example— were shown by John Vane to inhibit the enzyme prostaglandin H2 synthase (also called cyclooxygenase or COX), which catalyzes an early step in the pathway from arachidonate to prostaglandins and thromboxanes (Fig. 10-18 see also Box 21-2). 

T Aspirin (acetylsalicylate Fig. 21-15b) irreversibly inactivates the cyclooxygenase activity of COX by acetylating a Ser residue and blocking the enzyme s active site, thus inhibiting the synthesis of prostaglandins and thromboxanes. Ibuprofen, a widely used nonsteroidal antiinflammatory drug (NSAID Fig. 21-15c), inhibits the same enzyme. The recent discovery that there are two isozymes of COX has led to the development of more precisely targeted NSAIDs with fewer undesirable side effects (Box 21-2). 

FIGURE 21-15 The "cyclic" pathway from arachidonate to prostaglandins and thromboxanes, (a) After arachidonate is released from phospholipids by the action of phospholipase A2/ the cyclooxygenase and peroxidase activities of COX (also called prostaglandin H2 synthase) catalyze the production of PGH2/ the precursor of other... 

Unlike the hormones described above, they are not synthesized in advance and stored they are produced, when needed, from arachidonate enzymatically released from membrane phospholipids by phospholipase A2 (see Fig. 10-18). The enzymes of the pathway leading to prostaglandins and thromboxanes (see Fig. 21-15) are very widely distributed in mammalian tissues most cells... 

---