Substrate interaction with 5α-reductase enzyme: Influence of the 17β-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 17β-side chain on the inhibitory activity on the enzyme 5α-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 17β-side chain.