Design and synthesis of monoaryl-substituted salicylaldoximes as new selective agonists of estrogen receptor beta

Estrogens are hormones whose effects are mediated by two receptor subtypes: ERα and ERβ. While Erα plays a well established role in mediating the "classical" estrogen activity, the physiological role of ERβ is becoming clearer in recent years. The actually proposed roles include: antiproliferative function, regulation of apoptosis and modulation of the immune response. Moreover, ERβ-selective agonists (SERBAs: selective estrogen receptor beta agonists) are very promising in therapeutic areas such as prostate hyperplasia and cancer, bone loss, arthritis, and intestinal inflammation. It is important to emphasize that a highly selective ERβ-stimulation could produce beneficial estrogen effects in some tissues, avoiding the undesired proliferative effects on breast and uterus, that are mediated by the other receptor subtype (ERα). In the research laboratory where I accomplished my PhD, monoaryl-substituted salicylaldoximes were developed as agonists of estrogen receptor β. These compounds were designed accordingly to a pharmacophoric model (characterized by a phenyl or aryl "central core", a phenolic ring and a para-hydroxy-phenolic function opposite to the phenolic ring) derived from structural analysis of natural non-steroidal compounds such as genistein or synthetic non-steroidal compounds such as diarylpropionitrile and indazole derivatives. The salicylaldoxime moiety was chosen as a bioisosteric replacement of the phenolic ring, because it is characterized by a six-membered pseudo-cycle that can form through an intra-molecular H-bond between the oximic nitrogen atom and the adiacent OH group. The aim of the work of this PhD thesis was to develop highly ERβ-selective salicylaldoximes with better agonist features, on the basis of previous results and applying a structural optimization process. The best results were obtained with compound 7 (bearing a chlorine substituent on the central scaffold) and 8 (bearing an additional 3'-fluorine substituent), both showing remarkable ERβ-affinities (even higher than that of estradiol in the case of 7) with Ki values in the sub-nanomolar range (Ki = 0.38 nM for 7 and 0.57 nM for 8) and high levels of ERβ-selectivity (β/α = 29 for 7 and 46 for 8). In transcriptional assays on ERβ, both compounds displayed a full agonist character. Moreover, compound 8 showed a selectivity in ERβ-activation (β/α EC50-selectivity ratio = 6.5) >50 times higher than that of estradiol itself.