PGE2 series

Since the above sequence was not applicable to the PGE2 series (side chain double bond), alternative methods had to be developed (17). Most of these procedures are general and indeed are more efficient for preparing cyclopentenolones than is the allylic hydroxylation process, even in those cases where the latter is applicable. An example of one of these newer methods, as applied to the preparation of the PGE2 precursor 53, is shown in Scheme 11 (18). The key feature of this process is the quantitative isomerization of the 3-hydroxy isomer 52 to the desired 4-hydroxycyclopentenone 53, presumably by aciH catalyz-ed addition-elimination reactions. That the 3-isomer is the synthetic equivalent of the 4-isomer creates additional valuable synthetic approaches to this critical synthon. 

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. 

Merck s L-651,896 (54) was the lead compound from a series of dihydro-benzofuranols [158]. L-651,896 inhibited cRBL (1 //M) as well as platelet 12-LO (5.9 /zM). In zymosan-stimulated mouse macrophages, both LTC4 and PGE2 release were inhibited (0.1 //M and 1.1 //M, respectively) similar potency was seen in rat and human ISN. Potent topical activity in AAE was seen, with LT production and oedema both inhibited at 20-30 nM/ear. LT levels were also reduced in mouse oxazolone contact sensitivity, but in this... 

Figure 11.26 The structures of the prostaglandin E series produced from three polyunsaturated fatty acids containing 20 carbon atoms but a different number of double bonds. The number of double bonds in the three different acids produces prostaglandins of the E series with a different number of double bonds outside the cyclopentane ring. It is this number which influences the function of the prostaglandin and similarly the function of prostacyclins and thromboxanes (see text). Note, PGEi has one double bond, PGE2 has two double bonds and PGE3 has three double bonds outside the cyclopentane ring.

Prostaglandins of 2 series PGA2, PGE2, PGp2a, PGI2 TXA2, LTB4... 

The number after the capital letter is usually written as a subscript and is used to designate the number of unsaturated bonds in the PG side chains and not within the ring structure itself. In PGEi, for example, a double bond exists between C-13 and C-14 in the 2 series (PGE2), a double bond exists between C-13 and C-14 and between C-5 and... 

It should be noted that, whereas most of the agonists described at EP, receptors are obvious derivatives of PGE2 (with the exception of iloprost), none of the antagonists thus far described bear any clear chemical resemblance to E series prostaglandins. 

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