Biosynthesis

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Chapter: Medicinal Chemistry : Prostaglandins

PGs are found in virtually all the tissues and organs. They are autocrine and paracrine lipid mediators that act on platelet endothelium, uterine tissues, and mast cells among others.


BIOSYNTHESIS

PGs are found in virtually all the tissues and organs. They are autocrine and paracrine lipid mediators that act on platelet endothelium, uterine tissues, and mast cells among others. The biosynthesis of PGE and PGF has been thoroughly established and both of them are derived from arachidonic acid. Two types of pathways have been proposed and are designated as follows:

1.           Cyclooxygenase pathway

2.           Lipoxygenase pathway

 

CYCLOOXYGENASE PATHWAY


Arachidonic acid is derived from dietary linoleic acid. It is present as a conjugated component of the phospholipid matrix of the most cellular membrane. Release of free arachidonic acid is due to the stimulation of phospholipase enzyme in response to some traumatic events (tissues damage, toxin, exposure, and hormonal stimulation). The first step in this pathway is the interaction of arachidonic acid with PGH synthase, a haemoprotein, that catalyses both the addition of oxygen and subsequent reduction (peroxide activity) of the 15th position of hydroperoxide to 15(s) configuration alcohol prostaglandin H2 (PGH2). PGH synthase is also called as cyclooxygenase I (COX-1) or cyclooxygenase II (COX-2). NSAIDs inhibit PGs synthesis; leading to relief of the pain, fever, and inflammation.

PGH2 serves as a substrate for specific enzymes, leading to the production of various PGs, TXA2, and PGI2. While PGE2 is formed by the action of endoperoxide isomerase on PGH2 and PGD2 by the action of isomerase or glutathione-s-transferase on PGH2. PGF2 is formed from PGH2 via endoperoxidase reductase. Thromboxane synthetase acts on PGH2 to produce thromboxane A2.

 

LIPOXYGENASE PATHWAY


Lipoxygenase are a group of enzymes that oxidize polyunsaturated fatty acid possessing two cis double bond separated by a methylene group to produce lipid peroxides. Arachidonic acid is metabolized to form a number of hydroperoxy eicosatetraenoic acid (HPETE) derivatives. These enzymes differ in the position at which they peroxidize arachidonic acid and in the tissues specificity. For example, platelets possess only 12-lipoxygenase, whereas leukocytes possess both 12-lipoxygenase and 5-lipoxygenase. Leukotriens are products of the 5-lipoxygenase pathways and are divided into major classes.

Hydroxylate eicosotetraenoic acid (LTs) is represented by lymphotoxin β4 (LTB4) and peptido leukotrienes (PLTs), such as leukotriene C4 (LTC4), leukotriene D4 (LTD4), and LTE4. Lipoxygenase produces leukotrienase from 5-HPETE. Lysine epsilon-aminotransferase (LAT) synthetase converts 5-HPETE to unstable epoxide termed leukotriene A4 (LTA4) that may be converted by the enzymes into the leukotriene, LTB4 or by LTC4 to other leukotrienes (e.g. LTD4, LTE4, and LTF4), and reconjugation with glycine and glutamic acid, respectively.

 

SAR of PGs


In the upper chain: Methyl esters (misoprostol), sulphonamide (sulprostone), and hydroxyl group (rioprost) possess greater activity than natural PGs.

In the cyclopentane ring: Variation in the cyclopentane ring results in a reduction in the PG activity. Enlargement of the ring or reduction of the ring leads to inactive compounds. Replacement of the carbon atom of cyclopentane ring by O, S, and N also leads to inactive compounds. Replacement of 9-keto group with = CH2 group gives active (metenprost) PG.

In the lower chain: C-15 hydroxyl group is protected (from metabolism) by the introduction of methyl group at C-15 and gem dimethyl group at C-16. The shifting of C-15 hydroxyl to C-16 position increases the metabolic stability of alkoxy, phenoxy (enprostil, sulprostone) analogues, and they are more active than natural PGs. Introduction of acetylinic group at C-13 and C-14 increase the leuteolytic activity.

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