Prostanoids

Early efforts to turn this process into a practically feasible general strategy were moderately successful [8]. Although the conjugate addition of organocopper 

Concerned with the need for an exhaustive multistep preparation of the required alkenylcopper or alkenylzinc intermediates, which are traditionally accessed from alkenyllithum precursors derived from alkynes, Lipshutz and Wood developed a 

Transmetallation of 12 with a catalytic amount of the higher order cyanocuprate Me2Cu(CN)Li2, in the presence of Me3ZnLi and with slow addition of enone 7 led first to the initial conjugate addition product 14, then to zinc enolate 15 after Cu-to-Zn transmetallation. The third component, the electrophile, either an aide- 

Several interesting variants of the Noyori three-component reaction strategy to prostaglandin natural products have been reported in the past five years. Only a representative selection of the most recent ones will be described. 

Bn = benzyl, THF = tetrahydrofuran, Ms = methanesulfonyl, DMAP = 4-dimethylamino-pyridine, TBS = t-butyldimethylsilyl. 

This chapter presents the main biosynthetic pathways for prostanoid formation, mechanisms of prostanoid action via specific receptors and, finally, the biological and pharmacological roles of individual prostaglandins, prostacyclins and thromboxanes. 

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Leukotrienes and Prostanoids. Arachidonic acid (AA) (213) and its metabohtes are iavolved ia cellular regulatory processes ia all three principal chemical signaling systems endocrine (see Hormones), immune, and neuronal (62). FoUowiag receptor activation or iacreased iatraceUular... 

The prostanoids produce effects via five main subclasses of GPCR DP, EP, FP, IP, and TP (63). The EP receptor exists ia four subtypes,... 

Table 14. Prostanoid and Leukotriene Receptor Agonists and Antagonists...

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). 

Fig. 1. Biosynthesis of prostanoids, where structures (5)—(8) are PGG2, PGH2, PGD2, and PGF2Q, respectively.

Detailed accounts of the biosynthesis of the prostanoids have been pubUshed (14—17). Under normal circumstances arachidonic acid (AA) is the most abundant C-20 fatty acid m vivo (18—21) which accounts for the predominance of the prostanoids containing two double bonds eg, PGE2 (see Fig. 1). Prostanoids of the one and three series are biosynthesized from dihomo-S-linolenic and eicosapentaenoic acids, respectively. Concentrations ia human tissue of the one-series precursor, dihomo-S-linolenic acid, are about one-fourth those of AA (22) and the presence of PGE has been noted ia a variety of tissues (23). The biosynthesis of the two-series prostaglandins from AA is shown ia Eigure 1. These reactions make up a portion of what is known as the arachidonic acid cascade. Other Hpid products of the cascade iaclude the leukotrienes, lipoxins, and the hydroxyeicosatetraenoic acids (HETEs). Collectively, these substances are termed eicosanoids. 

The melting points, optical rotations, and uv spectral data for selected prostanoids are provided in Table 1. Additional physical properties for the primary PGs have been summarized in the Hterature and the physical methods have been reviewed (47). The molecular conformations of PGE2 and PGA have been determined in the soHd state by x-ray diffraction, and special H and nuclear magnetic resonance (nmr) spectral studies of several PGs have been reported (11,48—53). Mass spectral data have also been compiled (54) (see Mass spectrometry Spectroscopy). 

Table 1. Physical Properties of Selected Prostanoids Derived from Arachidonic Acid...

AH the bis- and tri-unsaturated prostanoids display sensitivity to atmospheric oxygen similar to that of polyunsaturated fatty acids and Hpids. As a result, exposure to the air causes gradual decomposition although the crystalline prostanoids ate less prone to oxygenation reactions than PG oils or solutions. 

The PGs, PGI2 and TXA2 collectively exhibit a wide variety of biochemical and pharmacological activities and are iavolved ia both physiological and pathophysiological processes. However, the iadividual compounds show different overall activity profiles sometimes ia opposiag directions. Excellent reviews are available (59—64). A survey of some of the more important biological actions of the prostanoids foUow. 

Kidney Function. Prostanoids influence a variety of kidney functions including renal blood flow, secretion of renin, glomerular filtration rate, and salt and water excretion. They do not have a critical role in modulating normal kidney function but play an important role when the kidney is under stress. Eor example, PGE2 and -I2 are renal vasodilators (70,71) and both are released as a result of various vasoconstrictor stimuli. They thus counterbalance the vasoconstrictor effects of the stimulus and prevent renal ischemia. The renal side effects of NSAIDS are primarily observed when normal kidney function is compromised. 

The natural prostanoids have myriad biological effects and held great promise as potential therapeutic agents in numerous diseases. The natural prostanoids, however, also have three notable drawbacks which medicinal chemists have tried to overcome by molecular modification in order to produce acceptable dmg candidates. These drawbacks are rapid metaboHsm which results in lack of activity if taken orally and a short duration of action, numerous side effects due to their multiplicity of biological activities, and poor chemical stabiUty, a characteristic especially pronounced in PGE, -D, and -I stmctures. 

E. W. Horton, ia S. M. Roberts and F. Sclieinmann, eds.. Chemist, biochemistry, and PharmacologicalMctivity of Prostanoids, Pergamon Press, Oxford,... 

The organization of Part Two is according to structural type. The first section, Chapter Seven, is concerned with the synthesis of macrocyclic compounds. Syntheses of a number of heterocyclic target structures appear in Chapter Eight. Sesquiterpenoids and polycyclic higher isoprenoids are dealt with in Chapters Nine and Ten, respectively. The remainder of Part Two describes syntheses of prostanoids (Chapter Eleven) and biologically active acyclic polyenes including leukotrienes and other eicosanoids (Chapter Twelve). 

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. 

Two different routes to PCs via bicyclo[3.1.0]hexane intermediates are shown. In route 1 stereo- and position-specific addition of dichloroketene to a bicyclo[3.1.0]hexene provided the framework for elaboration to prostanoids. Route 2 featured stereospecific internal cyclopropanation and stereospecific Sn2 displacement of carbon to establish the prostanoid nucleus. 

The ci i-fused lactone A was resolved using (-t-)-l-(l-naphthyl)ethylamine to give the enantiomer required for the synthesis of prostanoids (Ref. 3). 

Thromboxane A2 is a potent platelet aggregating agent and vasodilator which undergoes rapid hydrolysis under physiological conditions (ti/2 32 sec. at pH 7 and 37°C). The synthesis of stable analogs was of interest for biological studies of this potent but evanescent prostanoid. 

Clavulones I and II are members of an unusual family of marine prostanoids from the coral Clavularia viridis which are biosynthesiied by a cationic (i.e. non-radical, non-endoperoxide) pathway. The total synthesis of clavulones I and II was accomplished from cyclopentadiene as SM goal. 

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