Hydroxytestosterones

A solution of 1 g of the dione in 200 ml of methanol at 0° is treated with 75 mg of sodium borohydride and the mixture is kept for 2 hr. After addition of 0.1 ml of acetic acid the mixture is concentrated to ca. 20 ml. Dilution with water gives 0.9 g of crystals which are chromatographed on 20 g of unwashed alumina. Elution with benzene-ether (40 60) yields 0.73 g of the methyl-hydroxytestosterone, mp 245-249°, which after crystallization from acetone has mp 255-256° [a] 111° (CHCI3). 

A second example can be found in the metabolism of the male sex steroid hormone testosterone. In addition to 7a -hydroxy- and 6a-hydroxytestosterone, CYP2A1 was also found to form A6-testosterone (136) (Fig. 4.69). Using selectively deuterated analogs (136), A6-testosterone was established as being formed in competition with 6o -hydroxytestosterone after initial hydrogen atom abstraction from C6 to form the common radical intermediate. Little, if any, A6-testosterone was found to be formed in competition with la-hydroxytestosterone after initial hydrogen abstraction from Cl. 

Testosterone, lljS-hydroxytestosterone, and a polyene alcohol, probably far-nesol, were found in the urine of male yellowfin Baikal sculpin (C. grewingkt). Synthesized in the testes, these compounds are excreted with milt (Katsel etal., 1992). 

Testosterone enol diacetate reacts with perchloryl fluoride in aqueous dioxane to give 6a- and 6/i-fluorotestostcrone 17-acetatc (18 X = a-F, /i-F) as the major products along with 6a- and 6/3-hydroxytestosterone 17-acetate (18 X = a-OH, /j-OH) and also 17/i-hydroxyandrostane-3,6-dione 17-acctate.31 The enamine derivative 3-(pyrrolidin-l-yl)estra-3,5-dien-17/i-ol can be fluorinated in methanol at —25 to — 35 C to provide 4/J-fluoro-3a-methoxycstr-5-ene-3/f 17/ -diol (19),32 while various 2-fluoro-3-oxoestranc derivatives 20 are formed by fluorination of a number of 3-methoxyestrane derivatives in tetrahydrofuran/water mixture with perchloryl fluoride.33... 

Further work by Stevenson et al. [105] has shown that 16a-hydroxytestosterone can be aromatized to oestriol via the 19-dihydroxy and 19-oxo derivatives, these changes being identical to those indicated above [104], in which an enzyme-peroxide intermediate was postulated (Fig. 14). Since the aromatase system is known to be catalysed by cytochrome P-450 [106], it is feasible that involvement of a P-450-peroxide species could be envisaged, not only in the C-10,19 cleavage but also in the preceding hydroxylations (Fig. 15). 

There is evidence [52] that there are at least two forms of cyt P-450 involved with aromatization. Likewise, there is evidence for different aromatases in human placenta which catalyse the production of oestrone and oestriol from 4-androstenedi-one and 16a-hydroxytestosterone, respectively. Each enzyme system has been subfractionated into its own cyt P-450 and cyt P-450 reductase [107]. This has been supported recently by Purohit and Oakey [108], who measured aromatase activity for 16a-hydroxy-4-androstenedione and 4-androstenedione in the presence or absence of the other substrate. 4-Androstenedione competitively inhibited aromatization of the 16a-hydroxy derivative, with apparent K, essentially the same as its apparent Km, suggesting that both substrates bind and are aromatized independently of each other. The 16a-hydroxy derivative competitively inhibited the aromatization of 4-androstenedione, thus presumably lowering the affinity of the aromatase for the latter. 

Intramolecular alkylation occurs when 19-hydroxytestosterone (178) (as 17-acetate) is treated with any one of three reagent systems. Iodine and acetone, for example, give 4/8- and 6/3-aIkylated products (179) and (180). The reactions... 

CYP3A 4-6P-hydroxytestosterone hydroxylase activity 4- erythromycin N-demethylation CYP3A protein expression and activity 4- in cirrhosis [38, 39, 55]... 

A green cell suspension culture of Marchantia polymorpha, a liverwort, was shown to convert testosterone (Fig. 6.4) to 6(3-hydroxytestosterone and epitestosterone to androst-4-ene-3,17-dione (Hamada et at, 1991). The same culture was able to reduce the C-17 carbonyl of androst-4-ene-3,17-dione. It... 

Introduction of a 9 -fluoro substituent (S-19) into 17a-methyl-l 1/3-hydroxytestosterone (S-18) will increase the androgenic and anabolic activities. The fact that this increase is due to the 9a-fluoro substituent becomes evident by comparing the effect of 9a-fluoro substitution (S-25) into 17a-methyl-l l-ketotestosterone(S-24). 

X-Ray diffraction studies are reported for a number of steroidal compounds. 2,2,6) -Trichlorotestosterone acetate has an essentially normal half-chair conformation (1) of ring A. The earlier supposition of a half-boat conformation, based largely upon apparent abnormalities in o.r.d. and c.d. data, points to the need for a thorough re-examination of previously accepted views on the chiroptical properties of conjugated enones (see p. 234). In contrast, 2)8-hydroxytestosterone (as the 2-acetate 17-chloroacetate) has ring a in an inverted half-chair conformation (2), the C(2)—O bond being pseudo-equatorial and nearly eclipsed with the... 

Oxidations of hydroxy ketones to diketones occur frequently in steroidal alcohols. If the alcoholic group, usually secondary, is remote enough from the keto group, its oxidation takes place independently and is achieved by the same reagents that are used for the oxidation of alcohols. A solution of chromium trioxide in aqueous sulfuric acid oxidizes 5-pregnen-3p-ol-20-one in acetone solution at room temperature within 2-5 min to 5-pregnen-3,20-dione in 90% yield [579]. Similarly, lip-hydroxytestosterone 17-acetate is transformed by chromium trioxide in 80% acetic acid at room temperature in 30 min into 11-ketotestosterone 17-acetate in 92% yield [807]. 

Figure 2 Effect of age on the 6ft-, la-, and 16a-hydroxylation of testosterone by rat liver microsomes. Liver microsomes equivalent to 333 mg of wet-weight liver from male rats were incubated with 700 m/xmoles of testosterone-4-C14 in a final volume of 5.7 ml for 7.5 min at 37°C in the presence of an NADPH-generating system. Formation of 6ft-hydroxytestosterone (6/f-OH), 7a-hydroxytestosterone (7a-OH), and 16a-hydroxytestosterone (16a-OH) was measured. Each value represents the average SE of three to six values where each value was obtained with the pooled livers from three to six rats. Taken from Ref. (36).

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