Substrate interaction with 5alpha-reductase enzyme: influence of the 17beta-chain chirality in the mechanism of action of 4-azasteroid inhibitors.
A series of steroidal compounds were synthesized in order to evaluate the possible influence of the configuration of a stereocenter in the 17beta-side chain on the inhibitory activity on the enzyme 5alpha-reductase (5AR). For this purpose diastereomerically pure 4-azasteroids epimers at C-22 were prepared (compounds 1-11) and tested as inhibitors of 5AR in "in vitro" tests. The obtained data showed that in most cases the couples of epimers possess a significant difference in their biological activity. We also considered, for the tested molecules, a series of chemico-physical parameters in order to find a possible correlation with their biological activity. The findings allowed us to propose a model of the binding site of 5AR which comprises also, for 4-azasteroid inhibitors, the configurational aspect of the 17beta-side chain.
Grisenti
P
P
Poli Industria Chimica SpA, Via Volturno 45/48, Quinto de Stampi, Rozzano, Milan, Italy. pgrisenti@poli.it
Magni
A
A
Olgiati
V
V
Manzocchi
A
A
Ferraboschi
P
P
Villani
V
V
Pucciariello
R
R
Celotti
F
F
D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000378:metabolism*; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001665:Binding Sites / Q000502:physiology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism; D008954:Models, Biological; D008968:Molecular Conformation; D051381:Rats; D013256:Steroids / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D058891:5-alpha Reductase Inhibitors; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D013256:Steroids; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase