18-Hydroxy-deoxycorticosterone

The zona glomerulosa is responsible for the production of the mineralocorticoids aldosterone, deoxycorticosterone, and 18-hydroxy-deoxycorticosterone. Aldosterone promotes renal sodium retention and excretion of potassium. Its synthesis and release are regulated by renin in response to decreased vascular volume and renal perfusion. Adrenal aldosterone production is regulated by the renin-angiotensin-aldosterone system. 

Carboxymethyloxime formation is reported for a variety of 3-oxo- and 7-oxo-steroids, suitably protected at other oxo-groups (C-17 or C-20) where necessary. Syn- and anti-forms of carboxymethyloximes were separated by repeated t.l.c." The 6-carboxymethyloximino-derivative (479) of oestetrol was used as hapten in the production of a highly specific antiserum for oestetrol. " The synthesis of 6-oxo-oestetrol proceeded through known steps. RIA of 18-hydroxy-deoxycorticosterone (480) ° has been based upon the 3-carboxymethyloxime of the intact steroid, but 18-hydroxycorticosterone (481) was degraded by periodic acid to the y-lactone (482) before formation of its 3-carboxymethyloxime. The antiserum to this y-lactone responds equally to the y-lactone derived from 18-hydroxydeoxycorticosterone, but other corticosteroids did not interfere. 

The separation of endogenous 17- or 18-hydroxylated corticosteroids of the 21-hydroxylated 4-pregnen series was obtained by capillary electrophoresis of their charged borate chelate complexes (323). Aldosterone, 18-hydroxycorti-costerone, 18-hydroxy-deoxycorticosterone, cortisone, cortisol and 11-deoxycor-tisol are separated and resolved with 400 mM borate buffer at pH 9.0. The corticosteroid/borate chelation complex as indicated by CE data correlated well with 11 B-NMR. The separation of corticosteroids and benzothiazin analogs were studied by MEKC and a comparison with CZE was made (324). Bile salts, which have a similar carbon skeleton to the corticosteroids, were used for the separation of these steroids. A short analysis time, 15 min, and a high number of theoretical plates (150,000-350,000) were obtained. Sodium cholate was found to be very effective. The MEKC method was applied to the determination of the drug substance in tablets and cream formulations. An internal standard method was used for quantitation. The purity of the drug substance was also determined. 

These war efforts led to the discovery of two major groups of corticoid hormones, the glucocorticoid and the mineralocorticoid hormones. The most active glucocorticoids are cortisone and cortisol. Both these hormones have anti-insulin effects but are without marked effect on sodium retention. Quite to the contrary, they may stimulate sodium and chloride excretion. Aldosterone has only mild corticoid effects, but it has a marked ability to influence the kidney to retain sodium. 17a-Hydroxy deoxycorticosterone, 19-hy-... 

Fluorination at Cja-position increases the mineralocorticoid activity of both Cji-hydroxy (hydrocortisone) and C -deoxy (deoxycorticosterone) compounds. 

Wittig-Horner reaction (see p. 241). Photolysis of the nitrite of the 21-chloro-20-hydroxy-compound (194) gave the 18-oximino-compound (195) which on Jones oxidation was converted into the chlorolactone (196). Hypoiodite reaction of the 21-chloro-20-hydroxy-compound (194) also gives the chloro-lactone (196) which with modification gives 18-hydroxy-11-deoxycorticosterone (see also ref. 198). 

Aldosterone production is initiated by 21-hydroxylation of pregnenolone in the adrenal glomerulosa, where there is no 17-hydroxylase activity. The product of hydroxylation of pregnenolone by P450c21 is 21-hydroxy-progesterone, also known as deoxycorticosterone (DOC). The quantity of aldosterone produced by the adrenal is only 1% of that of cortisol for this reason, not all patients with classic P450c21 deficiency manifest with salt wasting. 

Tautomerism involving hemiacetal bridges has been explored by C n.m.r. for aldosterone (16), 18-hydroxy-11-deoxycorticosterone (19), and 18-hydroxy-progesterone (18)." Aldosterone and its 21-acetate (17) each showed 32 lines in their broad-band proton-decoupled spectra, indicating the presence of both the... 

Iodo 20-oxo steroids are important intermediates for synthesis of 21-hydroxy 20-oxo steroids, e.g., dehydrocorticosterone and cortisone,711 also deoxycorticosterone 712 so the preparation of these a>iodo ketones by the following very interesting reaction with iodine should be noted ... 

Sample preparation 1 mL Serum -I- 100 pL water containing 5 pg/mL 2,3-diaminona-phthalene and 3.5 pg/mL 18-hydroxy-ll-deoxycorticosterone -I- 1 mL 250 mM NaOH 7 mL diethyl ether, shake on a rotary shaker for 15 min, repeat extraction. Combine the... 

Similar strategies have been used to develop inhibitors that target the C-18 hydroxylation involved in the biosynthesis of aldosterone . Thus, aldosterone analogs with C-18 iodomethyl, chloromethyl, allyl, propargyl, vinyl, and methyl-thiomethyl functionalities have been synthesized and some have been found to irreversibly inactivate the enzyme. An active site-directed 18-acetylenic deoxycorticosterone [21 -hydroxy-13(-2-)propy-... 

If a 17o -20-ketopregnane (e.g., 17a-deoxycorticosterone) is subjected to the action of a 17a-hydroxylating organism (e.g., Trickothecium roseum) the isolation of either a 17a-hydroxy-20-ketopr nene (e.g.. Compound S) or a 17/3-20 -ketopregnane (e.g., deoxycorticosterone) would give important evidence for the enolization hypothesis. Since the formation of the former would be an apparent violation of the rule for... 

Ap-58 Okada, M., Yamada, A., and Ishidate, J. Pharm. Soc. Japan 816 (1965). 7a-Hydroxylation of dehydroepiandrosterone with Gibberella saubinetti. 15a-Hydroxy-lation of progesterone, deoxycorticosterone, and testosterone with the same organism. 

P450 21A2 is the enzyme involved in the 21-hy-droxylation of progesterone and 17-hydroxy-progesterone, yielding deoxycorticosterone and 11-deoxycortisol from the two substrates, respectively (Fig. 9.12). The 21-hydroxylation reaction is an important step in the synthesis of glucocorticoids and mineralocorticoids, and de-... 

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