Prostaglandins stability

The same mixture of H and I was obtained starting with either of the geometrically isomeric radical precursors E or F. A possible explanation is based on the assumption of a common radical conformer G, stabilized in the geometry shown by electron delocalization involving the radicaloid p-orbital, the p-peroxy oxygen and Jt of the diene unit. The structure of the compounds H and I were determined by H NMR spectra and the conversion of H to diol J, a known intermediate for the synthesis of prostaglandins. 

An 8-phenylmenthol ester was employed as the chiral auxiliary to achieve enantioselectivity in the synthesis of prostaglandin precursors.83 The crucial features of the TS are the anti disposition of the Lewis acid relative to the alcohol moiety and a tt stacking with the phenyl ring that provides both stabilization and steric shielding of the a-face. 

Amin, M., Simultaneous determination of prostaglandins (PG) E2, A2 and B2 and stability studies of PGE2 in pharmaceutical preparations by ion-pair reversed phase HPLC, Pharm. Acta. Helv., 64, 45, 1989. 

An excellent carrier is needed to deliver a sufficient amount of prostaglandins to the diseased site. Liposomes have been studied for a long time as possible drug carriers. However, the clinical use of liposomes has delayed because of some difficulties in mass production, sterilization, stability and safety. Since 1980 we have attempted to use lipid microspheres (lipid emulsions) instead of liposomes as a better carrier for lipophilic drugs (7). 

For instance, the marked lack of stability of prostaglandins of the E series (26). [20] in acid as well as in basic medium, is due to the presence of a 3-hydroxyketone system in the structure which, under these conditions, is dehydrated to give in the first place the secondary prostaglandins of the A series (26a) and later on, under more drastic conditions, the prostaglandins of the B series (26b) (Scheme 4.6). 

Misoprostol (B) is a semisynthetic prostaglandin derivative with greater stability than natural prostaglandin, permitting absorption after oral administration. like locally released prostaglandins, it promotes mucus production and inhibits acid secretion. Additional systemic effects (frequent diarrhea risk of precipitating contractions of the Liillmann, Color Atlas of Pharmacology (... 

Glucocorticosteroids are the most potent antiinflammatory agents available. They stabilize lysosomal membranes and reduce the concentration of proteolytic enzymes at the site of inflammation. They promote the synthesis of proteins called lipocortins which inhibit phospholipase-A2 and thus inhibit production of arachidonic acid, leukotrienes and prostaglandins. Furthermore, the expression of COX-II and through that the inflammatory effects of the licosanoids is inhibited. Glucocorticosteroids reduce the release of histamine from basophils, decrease capillary permeability and cause vasoconstriction. Glucocorticosteroids stimulate the loss of calcium with the urine and inhibit the resorption of calcium from the gut. 

This beneficial effect of fluorination on hydrolytic stability has also been demonstrated with the synthetic prostaglandin SC-46275 (Fig. 70). This compound possesses an anti-secretory activity that protects the stomach mucous membrane. However, its clinical development was too problematic because of the instability of the tertiary allyl alcohol in acidic medium (epimerisation, dehydration, etc.). A fluorine atom was introduced on the C-16 methyl to disfavour the formation of the allylic carbocation. This fluorinated analogue possesses the same biological activity, but does not undergo any degradation or rearrangement, and itepimerises only slowly [165]. 

P.W. Collins, R.L. Shone, A.F. Gasieski, W.E. Perkins, R.G. Blanch , Stabilization of a prostaglandin tertiary allylic alcohol system by fluorine Synthesis, acid stability studies and pharmacology of a 16-fluoromethyl analog of SC-46275, Bioorg. Med. Chem. Lett. 2 (1992) 1761-1766. 

Figure 3.18 Enhancement of the hydrolytic stability of prostaglandin derivatives by fluorination. ...

The answer is a. (Hardman, p 914.) Misoprostol is a prostaglandin analogue of PGE with an affinity for the gastric mucosa. It stimulates the secretion of mucus and bicarbonate, enhances cell proliferation, preserves the microcirculation, and stabilizes tissue lysosomes. Misoprostol is approved by the FDA for protection against the ulcerogenic action of NSAIDs (not because it antagonizes NSAIDs). 

Retinoic acid is an effective treatment of acne vulgaris and is used topically. It stabilizes lysosomes, increases ribonucleic acid polymerase activity, increases prostaglandin E, cAMP and cGMP level. 

The analogue in which carbon replaces oxygen in the enol ring should of course avoid the stability problem. The synthesis of this compound initially follows a scheme similar to that pioneered by the Corey group. Thus, acylation of the ester (7-2) with the anion from trimethyl phosphonate yields the activated phosphonate (7-3). Reaction of the yhde from that intermediate with the lactone (7-4) leads to a compound (7-5) that incorporates the lower side chain of natural prostaglandins. This is then taken on to lactone (7-6) by sequential reduction by means of zinc borohydride, removal of the biphenyl ester by saponification, and protection of the hydroxyl groups as tetrahydropyranyl ethers. 

Retinoic acid has several effects on epithelial tissues. It stabilizes lysosomes, increases ribonucleic acid polymerase activity, increases prostaglandin E2, cAMP, and cGMP levels, and increases the incorporation of thymidine into DNA. Its action in acne has been attributed to decreased cohesion between epidermal cells and increased epidermal cell turnover. This is thought to result in the expulsion of open comedones and the transformation of closed comedones into open ones. 

Biologically active materials such as prostaglandin Ej have been reported to benefit from being incorporated into phospholipids-stabilized emulsions (Teagarden... 

The dioxopyrazolines are also acidic because of their enolic group (4,4-disubstituted analogues are inactive) and a recent example azapropazone (apazone) (184) inhibits prostaglandin synthesis. Its pharmacological properties are like those of phenylbutazone and it is also uricosuric. Anti-inflammatory 1,2-benzothiazine 1,1-dioxides such as piroxicam (185 R = 2-pyridyl) also have an acidic enolic group whose anion can be stabilized by... 

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