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Prostaglandins

Free pharmacy material
Prostaglandins

INTRODUCTION
Prostaglandins    were first discovered and isolated from human semen in the 1930s by Ulf von Euler of Sweden. Thinking they had come from the prostate gland, he named them prostaglandins. It has since been determined that they exist and are synthesised in virtually every cell of the body. Prostaglandins are like hormones in that they act as chemical messengers, but they do not move to other sites—they work right within the cells where they are synthesised.

The name ‘prostaglandin’ derives from the prostate gland. When prostaglandin was first isolated from seminal fluid in 1935 by the Swedish physiologist Ulf von Euler, and independently by M.W. Goldblatt, it was believed to be part of the prostatic secretions (in actuality, prostaglandins are produced by the seminal vesicles); it was later shown that many other tissues secrete prostaglandins for various functions.
Prostaglandins are unsaturated carboxylic acids, consisting of a 20-carbon skeleton that also contains a five-membered ring, and are based upon the fatty acid, arachidonic acid. There are a variety of structures—one, two, or three double bonds. On the five-membered ring there may also be double bonds, a ketone, or alcohol groups.
FUNCTIONS OF PROSTAGLANDINS
There are a variety of physiological effects:
  1. There may be activation of the inflammatory response, production of pain, and fever. When tissues are damaged, white blood cells flood to the site to try to minimize tissue destruction. Prostaglandins are produced as a result.
  2. Blood clots form when a blood vessel is damaged. A type of prostaglandin called thromboxane stimulates constriction and clotting of platelets. Conversely, PGI2 is produced to have the opposite effect on the walls of blood vessels where clots should not be forming.
  3. Certain prostaglandins are involved with the induction of labour and other reproductive processes. PGF causes uterine contractions and has been used to induce labour.
  4. Prostaglandins are involved in several other organs such as the gastrointestinal tract (inhibit acid synthesis and increase secretion of protective mucus); they increase blood flow in kidneys; and leukotrienes promote constriction of bronchi associated with asthma.
 BIOSYNTHESIS OF PROSTAGLANDINS
Prostaglandins are found in virtually all tissues and organs. They are autocrine and paracrine lipid mediators that act upon platelet, endothelium, uterine, and mast cells, among others. They are synthesised in the cell from arachidonic acid produced by phospholipase A2. The intermediate is then passed into either the cyclooxygenase pathway or the lipoxygenase pathway to form either prostaglandin and thromboxane or leukotriene. The cyclooxygenase pathway produces thromboxane, prostacyclin, and prostaglandin D, E, and F. The lipoxygenase pathway is active in leukocytes and in macrophages, and synthesises leukotrienes. Prostaglandins are released through the prostaglandin transporter on the cell’s plasma membrane.
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 NOMENCLATURE
Naturally occurring prostaglandins are classified according to their ring substituents.
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Prostaglandins A, B, and C are α- or β-unsaturated ketones, D and E are β-hydroxy ketones, and F are 1, 3-diols. The main classes are further subdivided in accordance with the number of double bonds present in the side-chain. This is indicated by subscripts 1 or 2—e.g., PGE1 and PGF2 α.
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An α-substituent is one projecting down from the plane of the molecule and a β-substituent is one projecting above the plane of the molecule. In PGF2α, the 9-hydroxyl group projects below the plane. The two arms (side-chains) are trans to each other in natural PGs. The carboxy-bearing upper arm is attached in the α-configuration.
 Synthesis of Prostaglandins
Prostaglandin E1   Miyano’s synthesis from acyclic precursor β
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Reaction between β-keto acid 11-methoxy-3,11-dioxoundecanoic acid and styryl glyoxal gives aldol, namely methyl 11-hydroxy-9,12-dioxo-14-phenyl-13-tetradecenoate. Aldol undergoes cyclization in presence of base to give cyclopentane, namely 7-(2-styryl-3-hydroxy-5-oxo-1-cyclopentenyl)heptanoic acid. Reaction of this with osmium tetroxide oxidizes the lower arm with cleavage to form 7-(2-formyl-3-hydroxy-5-oxo-1-cyclopentenyl)heptanoic acid. 3-Hydroxy group is protected as tetrahydropyranyl derivative, and treatment with aqueous chromous sulphate reduces the double bond to give cyclopentane dertivative. This on reaction with dimethyl-2-ketoheptyl phosphate gives olefin (Wittig reaction). Reduction of lower chain keto function leads to alcohol, and deprotection of 3-hydroxyl group done with treatment with oxalic acid affords PGE1.
Prostaglandin F   Corey’s synthesis from cyclopentane precursor
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Cyclopentadiene on reaction with chlorodimethylether in presence of sodium gives methoxymethyl ether derivative, which on reaction with 2-chloroacrylonitrile gives Diels-Alder adduct. This on treatment with base followed by heating gives bicyclic ketone, which on treatment with peracid undergoes Bayer-Villiger oxidation to give cyclic ester. Saponification of cyclic ester gives cyclopentane acetic acid derivative. Iodination gives diiodo derivative, in presence of base, one of halide converted to alcohol and cyclic ester formed by reaction between acetic acid moiety and alcoholic group. The free hydroxyl group is protected as acetoxy derivative; iodo group is removed by treatment with tributyl tin hydride. Reaction with boron tribromide deprotects ether; treatment with Collin’s reagent oxidizes primary alcohol to aldehyde. Reaction of this with phosphorous ylide undergoes Wittig reaction to form alkene. Reduction of lower chain keto function leads to alcohol, and cyclopentyl hydroxy group is protected as tetrahydropyranyl derivative. Reduction of lactone leads to lactol, and is further reacted with triphenyl phosphono pentanoic acid, and treatment with oxalic acid affords PGF.
 STRUCTURES OF THERAPEUTICALLY USEFUL PROSTAGLANDINS
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 SAR OF PROSTAGLANDINS
  1. In the upper chain: Methyl esters (misoprostal), sulphonamide(sulprostone), and hydroxyl group (rioprost) possess greater activity than natural prostaglandins.
  2. In the cyclopentane ring: Variation in the cyclopentane ring has led to reduction in PG activity. Enlargement of the ring or reduction of ring leads to inactive compounds. Replacement of carbon atom of cyclopentane ring by O, S, and N leads to inactive compounds. Replacement of 9 keto group with imagesgroup gives active (metenprost) PG.
  3. In the lower chain: The 15-hydroxyl group has been 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 metabolic stability. Alkoxy and phenoxy (enprostil, sulprostone) analogues were more active than natural PGs. Introduction of acetylinic group at C13-14 increases luteolytic activity.

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