Cyclic Ketoximes as Estrogen Receptorâ€ ß Selective Agonists.

The development of estrogen receptorâ€…ß (ERß)-selective agonists represents a therapeutic strategy against several kinds of cancers, but the high homology between the two receptor subtypes, ERα and ERß, makes the achievement of this goal very challenging. In the past, we developed salicylaldoxime- and salicylketoxime-based molecules that proved to bind well to ERß. In this paper, further structural evolution of the salicylketoximes is presented: two of the newly synthesized five-membered cyclic ketoximes bind with nanomolar affinities to ERß, and they show selectivity for this subtype over ERα. Their agonist character was confirmed by cell-free coactivator recruitment assays, in which we demonstrated the ability of these compounds to form an active complex with ERß capable of recruiting coactivator proteins; this indicated their efficacy as agonists. Finally, their potency and selectivity for ERß binding were rationalized by molecular-modeling studies.