István Tóth

Neighboring group participation ☆: Part 15. Stereoselective synthesis of some steroidal tetrahydrooxazin-2-ones, as novel presumed inhibitors of human 5α-reductase

During the alkaline methanolysis of 3beta-acetoxy-21-chloromethyl-pregn-5-ene-20beta-N-phenylurethane, and its p-substituted phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)tetrahydrooxazin-2-on-6-yl]androst-5-en-3beta-ol and its p-substituted phenyl derivatives are formed. The cyclization takes place with (N(-)-6) neighboring group participation. Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding delta4-3-ketosteroids. The structures of the new compounds were proved by IR, 1H and 13C NMR spectroscopy, using up-to-date measuring techniques such as 2D-COSY, HMQC, and HMBC. The inhibitory effects (CI50) of the delta4-3-ketosteroids on 5alpha-reductase were studied.

Steroselective synthesis of some steroidal oxazolines, as novel potential inhibitors of 17α-hydroxylase-C17,20-lyase

17beta-Oxazolinyl steroids 7a-g and 8a-g were synthesized. The Lewis acid-catalysed reactions of (20R)-3beta-acetoxy-21-azidomethyl-20-hydroxypregn-5-ene with substituted aromatic aldehydes led to the formation of 3beta-acetoxyandrost-5-enes substituted in position 17beta with oxazolinyl residues (7a-g). Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids yielded the corresponding Delta(4)-3-ketosteroids. The inhibitory effects (IC(50)) of both 3-hydroxy compounds 7a-g and their Delta(4)-3-keto counterparts 8a-g on rat testicular C(17,20)-lyase were investigated with an in vitro radioligand incubation technique. The 3-chlorophenyl- (8d), and the 4-bromophenyl-17beta-(2-oxazolin-5-yl)androst-4-en-3-one derivatives (8f) were found to be modest inhibitors (IC(50)=4.8 and 5.0 microM, respectively).

Stereoselective synthesis of some 17β-dihydrooxazinyl steroids, as novel presumed inhibitors of 17α-hydroxylase-C17,20-lyase

Abstract 17β-Dihydrooxazinyl steroids 5a – l and 6a – l were synthetized. The acid-catalyzed reactions of 21-azidomethyl-20-hydroxy- and 21-hydroxymethyl-20-azidosteroids with substituted aromatic aldehydes led to the formation of androst-5-en-3β-ols substituted in position 17β with dihydrooxazine residues. The inhibitory effects of these compounds on rat testicular C 17,20 -lyase were investigated with an in vitro radioincubation technique.

Neighboring group participation: Part 17 Stereoselective synthesis of some steroidal 2-oxazolidones, as novel potential inhibitors of 17α-hydroxylase-C17,20-lyase

During the alkaline methanolysis of 3beta-acetoxy-21-chloropregn-5-ene-20beta-N-phenylurethane (4a), and its 4-monosubstituted (4b-e) and 3,5-disubstituted (4f) phenyl derivatives, cyclization occurs, in the course of which 17beta-[3-(N-phenyl)-2-oxazolidon-5-yl]androst-5-en-3beta-ol (5a) and its substituted phenyl derivatives (5b-f) are formed. The cyclization takes place with (N(-)-5) neighboring group participation. The reaction of 3beta-acetoxy-21-azidopregn-5-en-20beta-ol (3d) with triphenylphosphine gave 3beta-acetoxy-21-phosphiniminopregn-5-en-20beta-ol, which reacted in situ with carbon dioxide with the participation of the sterically favored 20beta-OH to give the unsubstituted steroidal cyclic carbamate (8). Oppenauer oxidation of the 3beta-hydroxy-exo-heterocyclic steroids (5a-f, 9) yielded the corresponding Delta(4)-3-ketosteroids (7a-f, 10). The inhibitory effects (IC(50)) of these compounds on rat testicular C(17,20)-lyase were investigated with an in vitro radioligand incubation technique. The N-unsubstituted 17beta-(2-oxazolidon-5-yl)-androst-4-en-3-one derivative (10) was found to be a potent inhibitor (IC(50)=3.0 microM).

Activity and inhibition of 3-beta-hydroxysteroid dehydrogenase/delta-5-4-isomerase in human skin

Activity and inhibition of 3 beta-hydroxysteroid dehydrogenase/delta 5-4-isomerase, a key example of biosynthesis of androgenic steroids, in human skin were studied. Whole-width dermal tissue specimens excised from various regions of the male and female body were investigated with an in vitro radioenzyme assay method using dehydroepiandrosterone as substrate. The Michaelis-Menten constant of the enzyme was found to be Km = 10nM and the maximal velocity was Vmax = 0.625 pmol produced 4-androstene-3,17-dione/mg protein/20 min. Activity of 3 beta-hydroxysteroid dehydrogenase/delta 5-4-isomerase in male inguinal skin (n = 8) was 0.132-0.412, in female abdominal skin (n = 4) 0.140-0.255, in perineal skin (n = 4) 0.138-0.962 pmol/mg protein/20 min. The synthetic steroids cyproterone acetate, 4-MA and epostane proved to be potent inhibitors, IC50 values were 150, 6.2 and 1.45 nM, respectively.

Low-Dose Aminoglutethimide Therapy without Glucocorticoid Administration

Eleven postmenopausal patients with advanced breast cancer were assessed for their response and endocrine changes to low-dose aminoglutethimide (250 mg twice a day) therapy without steroid administration. In 7 cases an objective response was registered; 1 patient had a stabilization of the disease lasting for 9 months. Significant falls in plasma estrogen and rises in plasma androgen levels were observed, while those of cortisol and ACTH remained essentially unchanged. No serious side effects occurred.

Configurational analysis and relative binding affinities of 16-methyl-5α-androstane derivatives

The four possible isomers 16beta-hydroxymethyl-5alpha-androstane-3beta,17beta-diol 1, 16alpha-hydroxymethyl-5alpha-androstane-3beta,17beta-diol 2, 16beta-hydroxymethyl-5alpha-androstane-3beta,17alpha-diol 3 and 16alpha-hydroxymethyl-5alpha-androstane-3beta,17alpha-diol 4 with proven configuration were converted into the corresponding 16beta-methyl-5alpha-androstane-3beta,17beta-diol 5, 16alpha-methyl-5alpha-androstane-3beta,17beta-diol 6, 16beta-methyl-5alpha-androstane-3beta,17alpha-diol 7, 16alpha-methyl-5alpha-androstane-3beta,17alpha-diol 8, furthermore into the 16beta-methyl-17beta-hydroxy-5alpha-androstane-3-one 13, 16alpha-methyl-17beta-hydroxy-5alpha-androstan-3-one 14, 16beta-methyl-17alpha-hydroxy-5alpha-androstan-3-one 15 and 16alpha-methyl-17alpha-hydroxy-5alpha-androstan-3-one 16. The steric structures of the resulting epimers were determined by means of 1H-, and 13C-NMR spectroscopy. In this way, comparison was possible with the C-16 epimers 5, 6 and 13, 14 prepared earlier by a different route, and the series of isomers could be completed with the steric structures of 16beta-methyl-17alpha-hydroxy-5alpha-androstan-3beta-ol 7 and 16alpha-methyl-17alpha-hydroxy-5alpha 8 and with their 3-keto derivatives 15 and 16. The relative binding affinities of the 16-methyl-5alpha-androstane-3beta,17-diols 5, 6, 7, 8 and 17-hydroxy-16-methyl-5alpha-androstan-3-ones 13, 14, 15, 16 were studied. The introduction of a 16-methyl substituent into 5alpha-androstane molecules substantially decreases the binding affinity to the androgen receptor and 16alpha-methyl derivatives were always bound more weakly than the 16beta-methyl isomers.