Corticosteroids, fluorination

J. Y. Godard, ki R. E. Banks and K. C. Lowe, eds.. Fluorine Medicines of the 21st Century, Paper 10, University of Manchester, Institute of Science and Technology, Manchester, U.K., 1994, for a review kitroduckig fluorine kito corticosteroids. 

Corticosteroids a chronic painless myopathy associated with the long-term use of corticosteroids is a particularly common example of drug-induced muscle disorder. It is almost certain that mild cases are overlooked because steroids are so frequently used to treat inflammatory myopathies such as polymyositis. Fluorinated steroids are particularly frequently implicated, and the incidence of drug-induced muscle disease is dose and time-related. The presence of muscle weakness can even complicate topical steroid therapy. Corticosteroid-induced myopathy is mediated via intramuscular cytosolic steroid receptors. The steroid-receptor complexes inhibit protein synthesis and interfere with oxidative phosphorylation. The myopathy is associated with vacuolar changes in muscle, and the accumulation of cytoplasmic glycogen and mitochondrial aggregations. 

The biological activity of a compound can often be affected dramatically by the presence of even a single fluorine substituent that is placed in a particular position within the molecule. There are diverse reasons for this, which have been discussed briefly in the preface and introduction of this book. A few illustrative examples of bioactive compounds containing a single fluorine substituent are given in Fig. 3.1. These include what is probably the first example of enhanced bioactivity due to fluorine substitution, that of the corticosteroid 3-1 below wherein Fried discovered, in 1954, that the enhanced acidity of the fluorohydrin enhanced the activity of the compound.1 Also pictured are the antibacterial (3-fluoro amino acid, FA (3-2), which acts as a suicide substrate enzyme inactivator, and the well-known anti-anthrax drug, CIPRO (3-3). 

Q57 Dexamethasone oral therapy is preferred during pregnancy to prednisolone. Dexamethasone is a fluorinated corticosteroid that does not cross the placenta readily. 

Dexamethasone is a fluorinated potent corticosteroid that readily crosses the placenta in pregnancy. Prednisolone is preferred during pregnancy since 88% is inactivated as it crosses the placenta. 

As soon as corticosteroids, such as cortisone, were used in the treatment of rheumatoid arthritis (glucocorticoid activity), important undesirable side effects appeared (sodium retention). In view of lowering the sodium retention, while increasing the anti-inflammatory activity. Fried performed various chemical modifications. Thus, he could observe that introducing a fluorine atom at the 9a position of the hydrocortisone acetate highly enhanced (11 times) the glucocorticoid activity, while the undesired sodium retention was lowered [130]. 

Other Addition Reactions.—At variance with previous reports, the palladium-catalysed reduction of 9a-fluoro-ll/3-hydroxy-A -and-A -corticosteroids proceeded stereospecifically to give the 5/8-isomers. The 9a-fluorine atom appears to be responsible for an increased folding of ring A towards the a-face, thus exposing the -face to the catalyst. 

The first example of the influence of a fluorine atom on the biological properties of a molecule was for a family of corticosteroids. This discovery has very important applications on a medicinal level the use of fluorinated compounds to modify biological properties for therapeutic applications. 

Fluorination of corticosteroids at C-9 or/and C-6 increases glucocorticoid activity, while mineralocorticoid activity, responsible for sodium retention (the main adverse effect of corticoids), is decreased (cf. Chapter 4). Fluorocorticoster-oids were the first fluorinated compounds to be used clinically. They are still major drugs against many inflammatory disorders rheumatoid polyarthritis, ORL (asthma, rhinitis), brain edema, dermatological, allergies, anaphylactic shock, Quincke s edema). 

Above all, Fried found out that introducing fluorine in corticosteroids had tremendous effects on their biological properties. After this discovery, this family of compounds became major drugs. 

Potent, fluorinated topical corticosteroid with comparable efficacytofluocinonide, diflorasone, amcinonide, betamethasone, dipropionate, and halcinonide cost should govern use... 

Mecfianism of Action A high-potency, fluorinated corticosteroid that decreases inflammation by suppression of migration of polymorphonuclar leukocytes and reversal of increased capillary permeability. The exact mechanism of the anti-inflammatory process is unclear. T fierapeuticEffect Decreases or prevents tissue response to the inflammatory process. 

Steroids. Spectra of 900 steroids W. Neudert and H. Ro ke, Atlas of Steroid Spectra. Berlin, Sprin-ger-Va-lag, 1965. Also A. P. Arzamastsev and D. S. Yashkina, Ultraviolet and Infra-red Spectra of Drugs, No. I, Steroids. Moscow, Meditsina, 1975. Ketosteroids F. Hodosan et al. Studii Cere. Chim., 1971,79,191-210 Yu. N. Levchucke i /.. Zh.prikl spektrosk, 1971, 14. 735-738. Corticosteroids and contraceptive steroids R J. Mesley, Spectrochim. Ada, 1966, 22, 889-917. Fluorinated corticosteroids G. Bellomonte, Ann. 1st. Super Sanita, 1973,9,121-128. 

Fluorinated corticosteroids were the first successful commercial products where useful modification of biological activity was achieved by introduction of a carbon-fluorine bond. Subsequently, the interest of the pharmaceutical industry in this approach has grown substantially and many new fluorine-containing products are available or are in advanced screening stages. 

Using SEM and x-ray microanalysis. King and co-workers [25] followed the distribution of topically applied sulfur (10% precipitated sulfur in an aqueous cream base), lead (20% w/w, subacetate solution), zinc (calamine lotion), and fluorinated corticosteroids after topical application on the forearm of a human subject. It was found that the amount of sulfur, zinc, and lead were at higher concentrations in the deeper layers of the SC with increasing application time. The fluorinated corticosteroids were not detected within the skin. Information was not provided about the exact depth of penetration or the amount of each element found at different depths within the SC. It was, however, acknowledged that the combined SEM and x-ray microanalysis... 

Therapy for the patient with atopic dermatitis can be divided into three distinct categories topical therapy for the skin, systemic therapy, and ocular therapy.Therapy for the skin includes the use of fluorinated corticosteroids such as triamcinolone or betamethasone or hydrocortisone... 

Adding a fluorine atom at C9 significantly enhances the potency of corticosteroids (see Chapter 7). The scheme used to introduce that function in an androstane (30-6 31-4) closely mirrors that which is used for the structurally more complex compounds. 

Fluticasone ointment 0.005% contains fluticasone propionate [(6(alpha),ll(beta),16(alpha),17(alpha))-6,9,-difluoro-ll-hydroxy-16-metliyl-3-oxo-17-(l-oxopropoxy)androsta-l, 4-diene-17-carbothioic acid, S-fluoromethyl ester], a synthetic fluorinated corticosteroid, for topical dermatologic use. The topical corticosteroids constitute a class of pri-... 

This drug is a highly potent fluorinated corticosteroid, which is used topically. 

Clocortolone pivalate is a topical, medium-potency, synthetic fluorinated corticosteroid. 

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