Configurational analysis and relative binding affinities of 16-methyl-5alpha-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.
Tapolcsányi
P
P
Department of Organic Chemistry, University of Szeged, Dóm tér 8, H-6720 Szeged, Hungary.
Wölfling
J
J
Tóth
I
I
Szécsi
M
M
Forgó
P
P
Schneider
G
G
D015113:Androstane-3,17-diol / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000378:metabolism*; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D020128:Inhibitory Concentration 50; D007536:Isomerism; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008968:Molecular Conformation; D051381:Rats; D011944:Receptors, Androgen / Q000378:metabolism*; D013329:Structure-Activity Relationship
D011944:Receptors, Androgen; D015113:Androstane-3,17-diol