A new diversity-oriented synthesis (DOS) methodology has been developed to generate different types of azacycles (oxazinones, oxazolidinones, and morpholines) from �-aminodiol steroid templates bearing a ketone functionality. A library of 16�,17�-oxazinone-estradiol derivatives obtained by this DOS approach unexpectedly provided a series of activator of 17�-hydroxysteroid dehydrogenase type 12 (17�-HSD12) (Figure 1). In fact, small molecule activators that directly modulate the activity of an enzyme are uncommon entities and such activators had never yet been identified for any 17�-HSD's. We hereby report the fortuitous discovery of a steroid derivative that caused an up to a 3-fold increase in the activity of 17�-HSD12. The stimulation of estrone (E1) to estradiol (E2) conversion has been characterized in intact and homogenized stably transfected HEK-293 cells and has also been observed in T-47D breast cancer cells. Structure-activity relationships closely linked to the nature of the substituent on the oxazinan-2-one ring of an E2 derivative emerged from this study. This activator will therefore be a useful tool to study this relatively unknown enzyme as well as the possible activation of other 17�-HSD family members.

Discovery of a first activator of 17�-hydroxysteroid dehydrogenases from diversity oriented synthesis of fused steroidal azacycle derivatives

248th National Meeting (2014)

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