Practical one-pot conversion of 17beta-estradiol to 10beta-hydroxy- (p-quinol) and 10beta-chloro-17beta-hydroxyestra-1,4-dien-3-one

An efficient one-pot procedure for the preparation of 10beta,17beta-dihydroxyestra-1,4-dien-3-one (p-quinol, 1, 75%) is reported, involving oxidation of 17beta-estradiol with potassium permanganate. Similar treatment of 17beta-estradiol with sodium chlorite led to 10beta-chloro-17beta-hydroxyestra-1,4-dien-3-one (2) in 44% yield along with smaller amounts 4-chloro-10beta,17beta-dihydroxyestra-1,4-dien-3-one (3), 2,10beta-dichloro-17beta-hydroxyestra-1,4-dien-3-one (4), and 4,10beta-dichloro-17beta-hydroxyestra-1,4-dien-3-one (5).     

A concise effective deprotection of spiro 3-cyclic thiaza ketal of steroidal 1,4-dien-3-one

An effective deprotective method of spiro 3-cyclic thiaza ketal of steroidal 1,4-dien-3-ones using alkyl vinyl ether in the presence of protic acid followed by the treatment of aqueous alkali was described. This novel protocol could be fulfilled under mild condition with high yield. The mechanism mediated by a carbonium ion formed in situ was clarified by the capture of the cleaved fragment.     

The identification of 14 alpha,17 beta-dihydroxyandrost-4-en-3-one monohydrate and 14 alpha,17 beta-dihydroxyandrosta-1,4-dien-3-one monohydrate, metabolites of androstenedione in Mucor piriformis.

The microorganism Mucor piriformis transforms androst-4-ene-3,17-dione into a major and several minor metabolites. X-ray crystallographic analysis of two of these metabolites was undertaken to determine unambiguously their composition and chirality. Crystals belong to the orthorhombic space-group P2(1)2(1)2(1), with a = 7.199(4) A and a = 6.023(3) A, b = 11.719(3) A and b = 13.455(4) A, c = 20.409(3) A and c = 20.702(4) A for the two title compounds, respectively. The structures have been refined to final R values of 0.060 and 0.040, respectively.     

Methandienone-I. A convenient method for the separation of 17alpha-methyl-17beta-hydroxyandrosta-i,4-dien-3-one and 17alpha-methyl-17beta-hydroxyanorosta-1,4,6-trien-3-one

17 α -Methyl-17 β -hydroxyandrosta-1,4-dien-3-one and 17α-methyl-17β-hydroxyandrosta-1,4, 6-trienone are found in the mother liquor of the reaction leading to the formation of the former from 17 α -methyl-17β -hydroxyandrosta-4-ene-3-one (I). This mother liquor usually discarded as waste product in the industrial production of 17α -methyl-17β -hydroxyandrosta-1,4-dien-3-one, can now be used for obtaining the two compounds separately using sodium metabisulfite.     

The identification of 17 -hydroxy-17-methyl-1,4-androstadien-3-one as a metabolite of the anabolic steroid drug 17 -hydroxy-17-methyl-1,4-androstadien-3-one in man

The more polar of the two major urinary metabolites of methandrostenolone, 17β-hydroxy-17-methyl-1,4-androstadien-3-one, in man has already been identified as 6β-hydroxymethandrostenolone, 6β, 17β-dihydroxy-17-methyl-1,4-androstadien-3-one. The other metabolite has now been identified as the 17-epimer of methandrostenolone, 17α-hydroxy-17-methyl-1,4-androstadien-3-one. The compound was isolated from the freely extractable neutral fraction of urine following the administration of 5 mg of the drug to normal men. The relevant chromatographic fractions from thin layer and gas liquid systems were identified by carbon skeleton chromatography. The 17-epimer has been synthesised, details of which are included, and the previously unidentified metabolite was found to be identical with the synthetic compound.     

Production of 20-carboxy-pregna-1,4-dien-3-one from sterols by mutants of Rhodococcus sp

By selection of microorganisms which preferentially attack the side-chain of either cholesterol or β-sitosterol (campesterol) we isolated five mutants of Rhodococcus sp. strain k-3 was obtained from the wild-type strain MIL 1037 and μ-9, μ-11, and μ-12 from MIL 1038, by mutagenic treatment and produced preferentially 20-carboxy-pregna-1,4-dien-e-one from β-sitosterol (campesterol) or cholesterol in good yield. The other mutant, μ-7, isolated from the wild-type strain MIL 1038 produced a new compound identified as 7aβ-methyl-1β-[1′,5′-dimethyl-6′-hydroxy-hexyl]-5-oxo-3aα-hexahydro-4-indanpropionic acid from cholesterol. A temporary accumulation of this compound was observed during the transformation of cholesterol. This compound could be used as an intermediate for the chemical synthesis of steroids with unnatural configurations.     

Synthesis of 5alpha-pregna-1,20-dien-3-one

5ALPHA-Pregna-1,20-dien-3-one has been synthesized from 3beta-hydroxy-5alpha-pregnan-20-one by reaction of the tosylhydrazone with butyllithium to introduce the vinyl moiety. Oxidation of the alcohol and treatment of the anion of the resulting ketone with benzeneselenenyl chloride gave the 2-phenylseleno derivative. This afforded the conjugated enone on oxidative elimination.     

Effect of 17 alpha-cyanomethyl-17 beta-hydroxy-estra-4, 9-dien-3-one on reproductive organs of the male laboratory mouse

The effect of subcutaneous administration (10, 15 and 20 mg/kg body weight/day, for 21 days; and 20 mg/kg body weight/day, for 28 days) of 17 alpha-cyanomethyl-17 beta-hydroxy- estra-4, 9-dien-3-one (STS 557) on the male reproductive organs of the Parkes strain mouse was investigated. The effect of the treatment on the testis was not uniform; both regressed and normal seminiferous tubules were observed in the same section of the organ. Furthermore, the histological changes observed in the seminiferous tubules in testes of STS 557--treated mice were not different in different dosage groups. In general, in moderately affected seminiferous tubules, the germinal epithelium was thin and consisted of Sertoli cells, spermatogonia, spermatocytes and spermatids; such tubules showed presence of many vacuoles in the epithelium. In severe cases, the tubules had collapsed and were lined by mainly Sertoli cells, spermatogonia and spermatocytes. The treatment also caused marked depression in motility and concentration of spermatozoa in cauda epididymidis, weight of accessory sex glands and in the levels of sialic acid and fructose in the epididymis and seminal vesicle, respectively. By 56 days of drug withdrawal, the alterations induced in the reproductive organs returned to control levels, suggesting that STS 557 treatment induces reversible alterations in the male reproductive organs of Parkes strain mouse.     

Biotransformation of (20S)-20-hydroxymethylpregna-1,4-dien-3-one by four filamentous fungi

Microbial transformation of (20S)-20-hydroxymethylpregna-1,4-dien-3-one (1) by four filamentous fungi, Cunninghamella elegans, Macrophomina phaseolina, Rhizopus stolonifer, and Gibberella fujikuroi, afforded nine new, and two known metabolites 2–12. The structures of these metabolites were characterized through detailed spectroscopic analysis. These metabolites were obtained as a result of biohydroxylation of 1 at C-6β, -7β, -11α, -14α, -15β, -16β, and -17α positions, except metabolite 2 which contain an O-acetyl group at C-22. These fungal strains demonstrated to be efficient biocatalysts for 11α-hydroxylation. Compound 1, and its metabolites were evaluated for the first time for their cytotoxicity against the HeLa cancer cell lines, and some interesting results were obtained.     

An approach to the mechanism of the potent antiglucocorticoid: 17 beta-hydroxy-11 beta-4-dimethylaminophenyl-17 alpha-propynyl-estra-4,9-dien-3-one

The effects of a new synthetic steroid, 17 beta-hydroxy-11 beta-4-dimethyl-aminophenyl-17 alpha-propynyl-estra-4,9-dien-3-one, classified under reference R38486 in the Roussel-Uclaf nomenclature [1], were investigated in two established rat hepatoma cell lines in order to gain information on the mechanism of action. The induction of tyrosine aminotransferase (TAT) and alanine aminotransferase (AAT) was totally abolished when R38486 was added with dexamethasone either on a 1-1 basis or on a 10-fold excess depending on the differentiation state of the cell. Binding studies showed a high affinity for the glucocorticoid receptor; however our "whole cell" study with [3H] R38486 indicates that only a low amount of antagonist-receptor complexes was translocated into the nucleus. Nuclear fractionation experiments showed that R38486, like the other antagonists studied, was located in the chromatin fraction where it may exert some definite role. Our observations based on whole cell experiments using physiological doses of glucocorticoid analogs indicate that the binding of activated antiglucocorticoid-receptor complexes to nuclear acceptor sites represents a physiologically significant process. Moreover the differences in the nuclear binding of antagonist-receptor- as compared to agonist-receptor-complexes may set off the machinery of antagonistic action.     

Some unreported by-products from the reaction of 1,4-dien-3-one steroids with 2-(methylammo)benzethiol/BF3

In a previous report, it was demonstrated that the 3-carbonyl of androsta-1,4-dien-3,17-dione (ADD) can be selectively protected with 2-(methylamino)benzethiol in the presence of BF3 in good yield. We explored the applicability of this method for other 1,4-dien-3-one steroids and got the desired protective products in different yield. Other than the usual protected products, we also got some unexpected by-products, including benzathiazol[4,3-b]-estra steroids. Their structures were determined by spectral analysis.     

Synthesis and testing of 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one: a highly potent orally active androgen

The title compound, 17a beta-hydroxy-7 alpha-methyl-D-homoestra-4,16-dien-3-one (3), was synthesized in five steps (17% overall yield) from 7 alpha-methylestrone methyl ether (5) and was found to possess oral androgenic activity, in excess of other known androgens, without using 17 alpha-alkyl substitution.     

A test of rats' tolerance for 3beta-acetoxyandrosta-1,5-dien-17-one ethylene ketal (ADEK), a new anti-androgen

Following the demonstration that the androgen activity of androsta-5-ene-3beta,17beta-diol (Adiol) is not inhibited by the anti-androgens currently used to treat prostate cancer, we sought agents that would inhibit the androgenic function of Adiol as well as of dihydrotestosterone. The steroid 3beta-acetoxyandrosta-1,5-dien-17-one ethylene ketal (ADEK) met this criterion. Its tolerance was assessed in rats by oral and by subcutaneous administration for four weeks. Neither route of ADEK administration resulted in any behavioral changes. There was no effect on weight gain during the 28 days of steroid intake and no effect on the weight of the kidneys, heart, liver, testes, adrenals or the ventral lobe of the prostate glands. The seminal vesicles of the treated rats were 23-29% and the weights of the anterior prostates of the respective groups were 17-26% smaller than the controls. In contrast, the dorsolateral prostates were increased 26-55% as compared with the controls. There were no detectable changes in the histology of the kidneys, hearts, livers, testes and adrenals of any of the rats, but both groups of ADEK-treated rats had mild atrophic changes in their seminal vesicles and in the ventral lobe of their prostate glands. Both ADEK-treated groups showed focal glandular epithelial hyperplasia in the dorsolateral lobes in comparison with the control group. Orally administered ADEK was rapidly converted to several metabolites, which were nearly completely cleared from the blood within 4h.