Cortisol, synthetic derivatives

Adrenocorticotropin is a peptide hormone produced in the anterior pituitary. Its primary endocrine function is to stimulate synthesis and release of cortisol by the adrenal cortex. Corticotropin can be used therapeutically, but a synthetic derivative is more commonly—and almost exclusively—used to assess adrenocortical responsiveness. A substandard adrenocortical response to exogenous corticotropin administration indicates adrenocortical insufficiency. 

Anecortave acetat (Retaane), a synthetic derivative of cortisol, has been delivered as a posterior juxtascleral depot to exert an angiostatic effect in patients with exudative age-related macular degeneration. The dmg is administered with a specially designed curved cannula at 6-month intervals. 

Synthetic derivatives of cortisol are often used to manage inflammatory conditions or to promote immunosuppression. The duration of action of several antiinflammatory steroids, their cellular effects j and biochemical actions, as well as the many and severe adverse effects are provided. 

I Synthetic derivatives of cortisol, the major endogenous glucocorticoid, are used j extensively in the management of inflammatory disorders and for their immuno-... 

Cortisol and its ketone derivative, cortisone, exert powerful anti-inflammatory effects in the body. These, or similar synthetic derivatives such as prednisolone, are used to treat inflammatory diseases such as rheumatoid arthritis and bronchial asthma. 

Synthetic glucocorticoids are prednisolone, prednisone, methylprednisolone, dexamethasone, betamethasone and triamcinolone (Table 13.2). Hydrocortisone is available as either succinate or phosphate salts for oral and intravenous administration. It is the drug of choice when a rapid effect is required, e.g. acute adrenal insufficiency, or as peri-operative replacement therapy. Prednisolone can also be given intravenously. It has about 0.8 of the mineralocorticoid activity of hydrocortisone. Prednisone is a prodrug that is converted to prednisolone in the body. For chronic therapy, synthetic steroids without mineralocorticoid activity are preferred, such as dexamethasone, betamethasone or triamcinalone. Beclo-metasone passes membranes poorly and is more active topically than when given orally. It is used as an aerosol for chronic rhinitis and asthma, and topically in severe eczema. Fludrocortisone is a synthetic halogenated derivate of cortisol that is used for its mineralocorticoid effect. 

T FIGURE 10-19 Steroids derived from cholesterol. Testosterone, the male sex hormone, is produced in the testes. Estradiol, one of the female sex hormones, is produced in the ovaries and placenta. Cortisol and aldosterone are hormones synthesized in the cortex of the adrenal gland they regulate glucose metabolism and salt excretion, respectively. Prednisolone and prednisone are synthetic steroids used as antiinflammatory agents. 

In 1948 cortisone was made from bile acids in quantity sufficient for clinical trial, and the dramatic demonstration of its power to induce remission of rheumatoid arthritis was published the following year. In 1950 it was realised that cortisone was biologically inert and that the active natural hormone is hydrocortisone (cortisol). Since then an embarrassingly large number of synthetic steroids has been made and offered to the clinician. They are derived from natural substances (chiefly plant sterols), the constitutions of which approach most nearly to that of the steroids themselves. A principal aim in research is to produce steroids with more selective action than hydrocortisone, which induces a greater variety of effects than desired in any patient who is not suffering from adrenal insufficiency. 

We now turn our attention to the synthesis of the fundamental lipid cholesterol. This steroid modulates the fluidity of animal cell membranes (p. 343) and is the precursor of steroid hormones such as progesterone, testosterone, estradiol, and cortisol. All 27 carbon atoms of cholesterol are derived from acetyl CoA in a three-stage synthetic process (Figure 26.6). 

Daxamathasone, 9a-fluora-I6a-methylpredniso-loue, 9a-fluoro-lip,I7,2I-trihydroxy-I6a-melhyl-pregna-l,4-diene-3,20-dione a synthetic pregnane derivative (see Steroids) which is highly antiinflammatory but has little mineralocorticoid activity. It is used to relieve arthritis. D. is synthesized from cortisol. 

Prednisolone 1,2-dehydrocortisol, 11, 17a,21-trihydroxy pregna-l,4-diene-3,20-dione, a synthetic steroid prepared by chemical or microbiological dehydrogenation of cortisol. It has powerful antiinflanunatoiy and antiallergic activity, very similar to that of prednisone (1,2-dehydrocortisone, the corresponding dehydro derivative of cortisone) both compounds are used in the treatment of disorders such as asthma, arthritis and eczema. 

For cortisol, a natural steroid hormone, position 3 of the ketone was chosen as the site of attachment for the organometallic moiety, since this site had also been used to derive the immunogen responsible for producing the antibodies employed in the assay. The synthetic strategy is summarized in Scheme 8.13. 

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