New ligands for estrogen receptor β

The estrogen receptors (ERs), which are members of a superfamily of nuclear receptors, are able to mediate the estrogen action in many organs and tissues (reproductive, skeletal, cardiovascular and central nervous). There are two subtypes of the estrogen receptor known as ER-alfa and ER-beta, that have different distributions in various estrogen target tissues and also have different functions. Selective estrogen receptor modulators (SERMs) are a special category of estrogens, that show an estradiol agonist-like action in some tissues, but antagonize estradiol in others. Despite the implication of ER-alfa in the “typical” estrogenic action has been established, the role held by beta is not yet fully understood. Sometimes, ER-beta seems to work against the activity of the other subtype ER-alfa, the iso-form that induce cancer growth in some organs (uterus, breast glands, ovary). Moreover, it is now known that stimulation of ER-beta by a beta-selective agonist may lead to therapeutic action in some hormone dependent tumours. Thus, molecules possessive agonist activity and selectivity for ER-beta (SERBAs) could be used in the treatment of these type of diseases. In a previous investigation by the laboratory where I carried out my PhD activity new potential selective estrogen receptor modulators (SERMs) with non-steroid structures were studied. It was shown that some oxime derivatives, comprised of a six-membered pseudocycle (A’) formed by an intramolecular H-bond, could isosterically replace one phenol ring (A) in ER ligands. Thus, a class of diarylsubstituted salicylaldoximes, that could efficiently bind the ERs, was developed. On the basis of the result obtained for the diarylsubstituted salicylaldoxime series, we envisaged the possibility of adapting the molecular approach above discussed to the recently developed ER-beta pharmacophoric model. So, the ER-beta pharmacophoric model have inspired the development and the synthesis of a new series of monoaryl-substituted salicylaldoximes, that could potentially show selective binding for ER-beta and a satisfactory potency as ER-beta agonists.