Dehydroepiandrosterone hydroxylation

Preparation of the newest of these, spirorenone (61), starts by 7-hydroxylation of dehydroepiandrosterone derivative Though this transformation has also been... 

The major androgen or androgen precursor produced by the adrenal cortex is dehydroepiandrosterone (DHEA). Most 17-hydroxypregnenolone follows the glucocorticoid pathway, but a small fraction is subjected to oxidative fission and removal of the two-carbon side chain through the action of 17,20-lyase. The lyase activity is actually part of the same enzyme (P450cl7) that catalyzes 17tt-hydroxylation. This is therefore a dual function protein. The lyase activity is important in both the adrenals and... 

Considering the excellent chemoselectivity observed in the allylic oxidation of dehydroepiandrosterone (Scheme 16), it was interesting to evaluate the selective allylic alcohol oxidation in the presence of a secondary saturated hydroxyl group using the BiCls/f-BuOOH system. This study was performed using androst-... 

In men, approximately 8 mg of testosterone is produced daily. About 95% is produced by the Leydig cells and only 5% by the adrenals. The testis also secretes small amounts of another potent androgen, dihydrotestosterone, as well as androstenedione and dehydroepiandrosterone, which are weak androgens. Pregnenolone and progesterone and their 17-hydroxylated derivatives are also released in small amounts. Plasma levels of testosterone in males are about 0.6 mcg/dL after puberty and appear to decline after age 50. Testosterone is also present in the plasma of women in concentrations of approximately 0.03 mcg/dL and is derived in approximately equal parts from the ovaries and adrenals and by the peripheral conversion of other hormones. 

The second method of preparation (shown in Scheme 2) depends on treating dehydroepiandrosterone (prepared from cholestrol or sitosterol) with acetylene to form the 17a-ethnyl-17p-hydroxy derivative, which is carbonated to the 17a-propionic acid. Reduction of the unsaturated acid in alkaline solution yields the saturated acid, which cyclizes to the lactone on acidification. Bromination to the 5,6-dibromo-compound, followed by oxidation of the hydroxyl group to the ketone, and then dehydro-bromination to the 7a-hydroxyl derivative, produces spironolactone when esterified with thiolacetic acid. 

SULT 2A and 2B sulfotransferase subfamily members sulfate the 3P-hydroxyl group of a variety of steroid hormones. Dehydroepiandrosterone (DHEA) is the prototypical substrate for the SULT 2 enzymes. However, other hydroxysteroids such as testosterone and its phase I hydroxylated derivatives are substrates for these enzymes. The SULT 2 sulfotransferases also are responsible for the sulfate conjugation of a variety of alcohols and xenobiotics that have undergone phase I hydro-xylation, including the polycyclic aromatic hydrocarbons (PAHs). The SULT 2 enzymes exhibit different patterns of tissue expression. SULT 2A1 is expressed primarily in the adrenal cortex, brain, liver, and intestine, while SULT 2B1 is expressed in the prostate, placenta, and trachea. 

The source of enzyme was microsomes prepared from liver and kidney cortex of rats. Some animals were treated with dehydroepiandrosterone to increase w-hydroxylation activity. 

Neutral corticosteroids are prone to the formation of acid adducts [M+RCOO] in negative-ion mode [20-21]. Abundant acetate adducts are observed for steroids with a relatively acidic hydroxyl group [22]. In negative-ion TSP ionization, Kim et al. [23] observed more abundant acid adducts with decreasing pK, of the acid. Marwah et al. [24] showed signal enhancement for a variety of steroids like dehydroepiandrosterone (DHEA) and related compounds due to the addition of low concentration of acid, i.e., typically 1-5 mmol/1 formic acid, 1-8 mmol/1 acetic acid, or 0.05-0.15 mmol/1 trifluoroacetic acid, while higher acid concentrations were found to compromise the response. Formic acid was the best choice for the neutral steroids, while acetic acid is preferred for sulfate conjugates. Post-column addition of 10 nmol/1 silver nitrate resulted in a ten-fold increase in the response for androst-5-ene-3p,17P-diol. [M+Ag] is observed instead of [M+H-HjO] [24]. 

In addition to the usual suffixes and prefixes just discussed, a few special prefixes are usually used for the semi-trivial names of the compounds. Thus the prefix dehydro- is used to indicate the loss of two hydrogen atoms from adjacent carbon atoms with the formation of a double bond (e.g, dehydroepiandrosterone). The prefix dihydro- or tetrahydro- indicates the addition of two or four hydrogen atoms to the molecule, respectively, as in dihydrocortisol and tetrahydrocortisol. The replacement of a hydroxyl group by hydrogen (COH CH) is denoted by the prefix deoxy- (or desoxy- [e.g., 11-deoxycorticosterone]). 

Treatment of dehydroepiandrosterone (13-3) with phosphorus pentachloride replaces the hydroxyl at position 3 with retention of configuration (13-4). It had been established prior to this work that catalytic reduction of unsaturation in steroids proceeds almost invariably from the bottom side to afford reaction products as their 5a epimers, as for example... 

The prototypical 17-alkylandrogen, 17- methyltestosterone, is prepared from dehydroepiandrosterone (DHEA 1-5) in two steps. Reaction of DHEA with an excess of methylmagnesium bromide gives the corresponding 17-methyl derivative (13-1) (Scheme 5.13). Oppenauer oxidation then converts the hydroxyl at C3 to a carbonyl group the olefin shifts into conjugation in the process to give mestanolone (13-2). 

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. 

CYP17A catalyzes both the 17a-hydroxylation of progesterone and subsequent cleavage of the C17-C20 bond to give androstenedione (Fig. 4.49). A similar transformation sequence accoimts for the conversion of pregnenolone to dehydroepiandrosterone. The favored mechanism for this reaction involves formation of the hydroperoxy hemiacetal with the ferric hydroper-oxy anion of the enzyme, followed by 0-0 bond homolysis, C-C bond homolysis, and finally recombination of the compormd II equivalent with... 

Martin C, Bean R, Rose K, Habib F, Seckl J (2001) CYP7B1 catalyses the 7a-hydroxylation of dehydroepiandrosterone and 25-hydroxycholesterol in rat prostate. Biochem J 355 509-515... 

In another pathway, 17a,20a-dihydroxycholesterol. or 17a,20a-trihydroxycholesterol is an intermediate between cholesterol and dehydroepiandrosterone. Androgens are also assumed to be synthesized in liver and nongonadal tissue from 21-hydroxylated derivatives such as 3j8,17a,21 -trihydroxy-5a-pregnane-11,20-dione and 11-deoxycorticosol, which by splitting of the side chain yield dehydroepiandrosterone or androst-4-ene- 3,17-dione. 

The 17-ketosteroids increased in the urine include dehydroepiandrosterone, androsterone, etiocholano-lone, and 11-hydroxy- and 11-oxy-derivatives. Thus, it would appear that as a result of the block in 21-hydroxylation, the rate of conversion of 17-hydroxy-progesterone to carbon 19 compounds is increased. These results indicated that the adrenals of these patients are capable of 11-hydroxylations in spite of the fact that 21-hydroxylation does not take place. As a result of 11-hydroxylation, 11-ketosteroids, and especially 11-ketopregnaetriol, are excreted in excessive amounts in the urine of patients with adrenogenital syndrome. Thus, 17-hydroxyprogesterone is direct-... 

---