János Julesz

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).

Central effects of tricyclic compounds on the endocrine system - An in vitro study

The present study involves the effects on corticotropin (ACTH) release of neuro- and thymoleptic tricyclic antidepressant compounds (TrcACs: chlorpromazine, promethazine, haloperidol, imipramine, amitriptyline) and their interactions with lysine-8-vasopressin (LVP) and corticosterone (B). As an in vitro model, 14-day monolayer pituitary cell cultures of Wistar rats were employed. The ACTH concentrations of the supernatant media were measured by radioimmunoassay. TrcACs augmented ACTH release; their combination with LVP, however, did not result in further stimulation; moreover, when combined with TrcACs + LVP, B did not inhibit, but rather paradoxically increased their ACTH-releasing action. As none of these phenomena were followed by relevant changes in intracellular cyclic adenosine monophosphate content, the mechanism of action may be proposed to involve a protein kinase C route.

Novel series of 17β-pyrazolylandrosta-5,16-diene derivatives and their inhibitory effect on 17α-hydroxylase/C17,20-lyase

The Claisen condensation of 3β-acetoxypregna-5,16-dien-20-one (1) with ethyl formate in the presence of sodium methylate in pyridine is known to lead to 3β-hydroxy-21-hydroxymethylidenepregna-5,16-dien-20-one (2) in good yield. With the methods described for the preparation of the saturated D-ring pyrazolyl series, the reactions of 2 with phenylhydrazine and its p-substituted derivatives in acetic acid resulted in mixtures of two steroidal regioisomers, the 1-aryl-3-pyrazolyl-(4a-e) and 1-aryl-5-pyrazolyl (5a-e) steroids. Compounds 4a-e are unknown in the literature. The arylpyrazoles produced were tested against 17α-hydroxylase/C(17,20)-lyase (P450(17α)) in vitro and neither of the regioisomers exerted efficient inhibition.

Synthesis of methoxycarbonylpyrazolylandrostene derivatives, and their potential inhibitory effect on androgen biosynthesis and cell proliferation

The Claisen condensations of 3β-acetoxypregn-5-en-20-one (1) and 3β-acetoxypregna-5,16-diene (7) with dimethyl oxalate are known to lead to 3β-hydroxy-21-methoxalylpregn-5-en-20-one (2) and 3β-hydroxy-21-methoxalylpregna-5,16-dien-20-one (8), respectively. The reactions of 2 with p-substituted phenylhydrazines afford pyrazol-5-yl derivatives (5) as main, and 3-yl regioisomers (4) as minor products. The corresponding reactions of 16-ene analogue 8 afford only pyrazol-5-yl regioisomer 9. Oppenauer oxidation of the pyrazolyl compounds yields the corresponding Δ(4)-3-ketosteroids. We investigated the antiandrogenic effects of new methoxycarbonylpyrazolyl compounds through determination of their in vitro inhibition of the activities of rat testicular C17,20-lyase, Δ(5)-3β-hydroxysteroid dehydrogenase (Δ(5)-3β-HSD) and 17β-hydroxysteroid dehydrogenase type 3 (17β-HSD3). A Δ(5)-3β-hydroxy compound in the D-ring-saturated androst-5-ene series bearing an unsubstituted phenyl group on the pyrazolyl heterocycle (5a) proved to be a potent inhibitor of Δ(5)-3β-HSD. The 4-methoxyphenyl derivative (5e) and the 3-oxo counterpart (6a) of 5a also displayed substantial inhibition. The other tested compounds exerted only weak inhibitory action against the enzymes investigated. The newly synthetized compounds were evaluated in vitro by means of MTT assays for antiproliferative activity against Hela (cervical carcinoma), A431 (skin epidermoid carcinoma) and MCF7 (breast adenocarcinoma) cells. In all four groups (3β-hydroxy- and 3-ketosteroids with saturated or unsaturated ring D), the most potent analogs contain a 4-tolyl or 4-methoxyphenyl group. Compound 5d exhibited substantial antiproliferative action against the three cell lines investigated, whereas 9d inhibited the growth of Hela cells markedly. The most noteworthy inhibition was exerted by 6a against A431 cells.

Asphyxia-induced release of α-melanocyte-stimulating hormone in newborn pigs

Abstract Asphyxia and reperfusion induced changes in the plasma and cerebrospinal fluid (CSF) concentrations of α-melanocyte-stimulating hormone (α-MSH) were studied in newborn pigs using a specific radioimmunoassay technique. Cardiovascular and metabolic failure induced by neonatal asphyxia resulted in a 3-fold, significant ( P P