Synthesis, binding affinity, and transcriptional activity of hydroxy- and methoxy-substituted...

An effective, unprecedented replacement of the prototypical phenolic 'A-ring' of estrogens with an oxime and a hydroxy-moiety of the salicylaldoxime derivative 3,4-diphenyl-substituted (1a) opened the way to study structure-activity relationships of a new class of estrogen receptor (ER)-ligands. Herein, we present a study of the ER binding properties and transcriptional activities of analogues of 3,4-diphenylsalicylaldoxime (1a). The introduction of p-OH and p-OMe groups on the phenyl substituents of 1a, as in compounds 1b-g, results in unique structure-activity profiles. The preparation of the hetero-disubstituted compounds (1b-e) was accomplished by a sequential introduction of different 3- and 4-aryl groups, obtained by exploiting the different reactivity of the bromine versus chlorine substituents on the precursor, 2-bromo-3-chloronitrobenzene (5), in the palladium-catalyzed cross-coupling reactions. The results of the biological tests show that the introduction of one hydroxy-group on the 3-phenyl substituent of the lead compound 1a improved the binding affinity on ERbeta (1c), whereas the introduction of the same group on the 4-phenyl substituent of 1a gave a compound (1e) with better affinity properties on ERalpha. The introduction of two hydroxyl groups in the para-position of both phenyl substituents of 1a, as in 1g, lowered the binding on both receptor subtypes. In transcription assays, the ERalpha agonist character of this class of ligands is enhanced by the presence of a p-hydroxy or p-methoxy in the 'distal' phenyl ring, whereas substitution on the other phenyl ring does not substantially modify the partial agonist character of 1a. Thus, results from the binding and transcription assays illustrate that this class of ER ligands has a distinct structure-activity profile on the two ER subtypes, being potent nearly full agonists on ERalpha and weak, partial antagonists on ERbeta.