Prostaglandins

The prostaglandins* are a group of modified C20 fatty acids first isolated from human semen and initially assumed to be secreted by the prostate gland. They are now known to occur widely in animal tissues, but only in tiny amounts, and they have been found to exert a wide variety of pharmacological effects on humans and animals. They are active at very low, hormone-like concentrations and can regulate blood pressure, contractions of smooth muscle, gastric secretion, and platelet aggregation. Their potential for drug use is extremely high, but it has proved difficult to separate the various biological activities into individual agents.

The basic prostaglandin skeleton is that of a cyclized C20 fatty acid containing a cyclopen-tane ring, a C7 side-chain with the car-boxyl function, and a C8 side-chain with the methyl terminus. Prostaglandins are biosynthe-sized from three essential fatty acids, A8,11,14-eicosatrienoic acid (dihomo-y-linolenic acid), A5,8,11,14-eicosatetraenoic acid (arachidonic acid), and A5,8,11,14,17-eicosapentaenoic acid, which yield prostaglandins of the 1-, 2-, and 3-series, respectively (Figure 3.16) (see below for principles of nomenclature). The three precursors lead to products of similar structure, but with varying levels of unsaturation in the two side-chains. Some of the structures elaborated from arachidonic acid are shown in Figure 3.17. In the first reaction, arachidonic acid is converted into prostaglandin G2 (PGG2) by an oxygenase (cyclooxygenase; COX) enzyme, which incorporates two molecules of oxygen, liberating a compound with both cyclic and acyclic peroxide functions. In arachidonic acid the methylene group flanked by two double bonds is susceptible to oxidation, probably via a free radical process. This may lead to incorporation of oxygen giving the proposed free radical intermediate. Formation of PGG2 is then depicted as a concerted cyclization reaction, initiated by the peroxide radical, in which a second oxygen molecule is incorporated. The acyclic peroxide group in PGG2 is then cleaved by a peroxidase to yield prostaglandin H2 (PGH2), which occupies a central role and can be modified in several different ways. These modifications can be rationally accommodated by initial cleavage of the cyclic peroxide to the diradical; alternative ionic mechanisms may also be proposed. Quenching of the free radicals by abstraction of hydrogen atoms gives rise to prostaglandin F2a (PGF2a), whilst capture and loss of hydrogen atoms would provide either prostaglandin E2 (PGE2) or prostaglandin D2 (PGD2). The bicyclic system in prostaglandin I2 (PGI2; prostacyclin) is envisaged as arising by involvement of a side-chain double bond, then loss of a hydrogen atom. Prostaglandin structures representative of the 1-series, e.g. PGE1, or of the 3-series, e.g. PGE3, can be formed in a similar way from the appropriate fatty acid precursor (Figure 3.16).

The basic skeleton of the prostaglandins is termed prostanoic acid, and derivatives of this system are collectively known as prostanoids. The term eicosanoids is also used to encompass prostaglandins, thromboxanes, and leukotrienes, which are all derived from C20 fatty acids (eicosanoic acids). Semi-systematic nomenclature of prostaglandins is based on the substitution pattern in the five-membered ring, denoted by a letter suffix (Figure 3.18), and the number of double bonds in the side-chains is given by a numerical subscript. Greek letters a and P are used to indicate the configuration at C-9, a indicating the substituent is below the plane (as

CO2H

CO2H

dihomo-y-linolenic (A8,11,14)

dihomo-y-linolenic (A8,11,14)

OH PGEj

CO2H

CO2H

OH PGEj

11 14

arachidonic (A5,8,11,14)

11 14

arachidonic (A5,8,11,14)

CO2H

CO2H

PGE2

PGE2

CO2H

11 14 17

eicosapentaenoic (A5,8,11,14,17)

11 14 17

eicosapentaenoic (A5,8,11,14,17)

CO2H

CO2H

pge3

pge3

methylene flanked by double bonds is susceptible to free radical oxidation; free radical reaction allows addition of O2 and formation of peroxide radical arachidonic acid arachidonic acid

OH PGH2

radical cleavage of cyclic peroxide

CO H cyclooxygenase 2 (COX)

concerted formation of cyclic peroxide, cyclopentane ring, and acyclic peroxide by addition of second molecule of O2; mechanistically, this is analogous to the first step but exploits the unsaturation; the peroxide radical finally abstracts a H atom co2h

cleavage of acyclic peroxide

COH peroxidase

OH PGH2

COH peroxidase

cyclic peroxide

CO2H O

PGF2a

PGF2a

CO2H

CO2H

CO2H

O-OH

acyclic peroxide

O-OH

acyclic peroxide

PGG2

pge2

CO2H O

pgd2

CO2H

CO2H

CO2H

CO2H

CO2H

CO2H

CO2H

Figure 3.17

pgi2

Figure 3.17

found in natural prostaglandins), and ß indicating abbreviated to PG. Prostaglandins A, B, and C the substituent is above the plane (as in some are inactive degradation products from the natural synthetic analogues). 'Prostaglandin' is usually prostaglandins.

11 13 15 17 19 prostanoic acid

1-series

2-series

3-series

CO2H

CO2H

CO2H

CO2H

CO2H

O-OH

PGG Figure 3.18

O-OH

PGG Figure 3.18

O"Cl

CO2H

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