Glucocorticoids

In order for glucocorticoid activity to be expressed, the presence of a hydroxyl group at position Cn/ and C17a in the structure of the pregnane system is very important. At the same time, in order for adequate mineralocorticoid activity to be expressed, an oxygen functional group is needed at C11 and C18, or else an absence of a hydroxyl functional groups are simultaneously needed at C11 and C17. In general, it is likely that the glucocorticoid binding with receptor sites should take place only in the simultaneous presence of the Cn/-hydroxyl group and a C17/-CO-CH2OH side chain of the steroid system. The presence of other bulky axially oriented /ยก-substituents in the molecule, as a rule, inhibits binding of steroid molecules with receptors, while analogs with equatorial a-substituents do not cause large problems.

The primary endogenic glucocorticoids are hydrocortisone and cortisone. Numerous synthetic analogs of natural glucocorticoids have been made and used, and they have turned out to be more effective, and currently they have almost completely replaced cortisone (prednisolon, prednisone, dexamethasone, and others).

Glucocorticoids are used orally, intravenously, intramuscularly, as inhalants, and in the form of ointments, creams, and so on.

Hydrocortisone: Hydrocortisone, 11/,17a,21-trihydroxypregn-4-en-3,20-dione (27.1.8), is synthesized in various ways and from various compounds containing a steroid skeleton. According to one of them, hydrocortisone is synthesized from dextro-pregnenolone. The double bond between C16 and C17 of dextropregnenolone is oxidized using hydrogen peroxide in a base, forming an epoxide 27.1.1. Interacting this with hydrobromic acid opens the epoxide ring, forming 16-bromo-17-hydroxydextropreg-nenolone (27.1.2). The resulting bromo derivative undergoes debromination by hydrogen using a palladium on carbon catalyst, and then the secondary hydroxyl group undergoes esterification using formic acid in the presence of p-toluenesulfonic acid, giving 3-formyloxy-17-hydroxydextropregnenolone (27.1.3). The resulting 3-formyloxy-17-hydroxydextropregnenolone undergoes bromination by bromine, which results in bromination of the C4-C5 double bond and the methyl group of acetyl moiety, which forms a tribromo derivative 27.1.4. Reacting the product with sodium iodide results in dehalogenation of the resulting vicinal dibromide, during which the double bond is simultaneously shifted into the position between carbon atoms C5 and C6 that gives the bromoketone 27.1.5. This is reacted with potassium acetate and then with acetic anhydride in the presence of p-toluenesulfonic acid, forming a diacetate 27.1.6. Taking into account that unlike acetates, formates are easily oxidized and give exactly the same products as do the corresponding alcohols, the resulting diacetate is oxidized in an Oppenauer oxidation reaction, using aluminum isopropoxide and cyclohexanone as a hydrogen acceptor. During this, isomerization of the double bond into the primary position between C4 and C5 simultaneously takes place, forming a stable, conjugated vinylketone, after which the acetyl protection of both hydroxyl groups is hydrolyzed using potassium hydroxide, giving 17-hydroxy-11-deoxycorticosterone (27.1.7). This undergoes microbiological oxidation at position C1, forming the desired hydrocortisone (27.1.8). Side reactions of microbiological oxidation using the very same microorganisms can cause hydroxylation of steroids in different positions, using easily accessible progesterone [1-5] as an initial substance [1-5].

CH3 C=O

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