Determination of rat 5alpha-reductase type 1 isozyme activity and its inhibition by novel steroidal oxazolines.

The 5alpha-reductase type 1 isozyme is a key enzyme in the metabolism of the androgen steroid hormones and inhibitors of this enzyme represent a new pharmacological treatment for several androgen dependent diseases. We developed a radiosubstrate in vitro incubation method for the determination of 5alpha-reductase type 1 activity using rat liver microsomes as an enzyme source. With this method we have studied the inhibiting activity of novel (5' S)-17beta-(4,5-dihydrooxazol-5-yl)androst-5-en-3-one compounds containing various derivatized phenyl substituents coupled to the exo -heterocyclic moiety.

Steroselective synthesis of some steroidal oxazolines, as novel potential inhibitors of 17alpha-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.

Neighboring group participation Part 17 Stereoselective synthesis of some steroidal 2-oxazolidones, as novel potential inhibitors of 17alpha-hydroxylase-C(17,20)-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).

Stereoselective synthesis of some 17beta-dihydrooxazinyl steroids, as novel presumed inhibitors of 17alpha-hydroxylase-C17,20-lyase.

17beta-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-3beta-ols substituted in position 17beta with dihydrooxazine residues. The inhibitory effects of these compounds on rat testicular C(17,20)-lyase were investigated with an in vitro radioincubation technique.