Monoaryl-Substituted Salicylaldoximes as Ligands for Estrogen Receptor β

Abstract

Salicylaldoximes possess a hydrogen-bonded pseudocyclic A' ring in place of the typical phenolic A ring that is characteristic of most estrogen receptor (ER) ligands. Monoaryl-substituted salicylaldoximes were obtained by replacing the phenol moiety (ring A) of the ERbeta pharmacophore with the pseudocycle A' ring, which has previously been shown to behave as a bioequivalent of phenols in nonselective ER ligands. In this series, small substituents (CH 3, CN, Cl) were introduced into the central phenyl scaffold. An efficient sequential halogen-selective double cross-coupling reaction was developed for the synthesis of the methyl-substituted ER ligand. The measured ERbeta affinity proved to be very sensitive to the effect of central core substituents. The binding affinities of the compounds herein reported were in good agreement with the results of computational docking analysis. The chloro-substituted derivative showed the highest beta affinity and selectivity, and it also proved to be an ERbeta partial agonist with an EC 50 of 11 nM.

Selective and potent agonists for estrogen receptor beta derived from molecular refinements of salicylaldoximes

“…This selectivity had already been demonstrated for other oxime analogues previously reported [13,14,16,17], and it was confirmed here by the chemical shift values of the oxime protons of all the new products, which were always found downfield from 8 ppm (δ ≥ 8, see experimental section) [20]. …”

“…2) by progressively refining the substitution pattern (compounds 1a , c , d ) [13,14], and we confirmed the detrimental effect of a second aryl substituent on ERβ binding ( 1b ) [16]. However, even the best Salaldox A members proved to be only partial agonists for ERβ, since their maximal activation values, compared to estradiol, were of 60% for 1c and 85% for 1d [13,14].…”

“…We recently reported on two restricted series of monoaryl-substituted salicylaldoximes bearing a para -hydroxylated aryl substituent at either position 4 ( Salaldox A ) [13,14] or 5 ( Salaldox B ) [14] of the central ring. These were inspired by a consolidated pharmacophore model originally developed for indazole derivatives [15] (Fig.…”

“…2) by progressively refining the substitution pattern (compounds 1a , c , d ) [13,14], and we confirmed the detrimental effect of a second aryl substituent on ERβ binding ( 1b ) [16]. However, even the best Salaldox A members proved to be only partial agonists for ERβ, since their maximal activation values, compared to estradiol, were of 60% for 1c and 85% for 1d [13,14]. Moreover, the beta-selectivities shown by these two compounds in functional assays were considerably less than their ERβ-selectivities in binding assays, probably because of differences in the manner in which the ERα- and ERβ-ligand complexes interact with various cellular coregulators, which can act as modulators of ligand potency.…”

In Silico Prediction of Estrogen Receptor Subtype Binding Affinity and Selectivity Using Statistical Methods and Molecular Docking with 2-Arylnaphthalenes and 2-Arylquinolines

“…The key issue in the design of new selective ER ligands is to explore the properties of the chemical structure in combination with its ability of inducing a pharmacological response as a consequence of receptor-binding. Great advances have been made in recent years because of multiple structurally diverse compounds were synthesized and have been shown to exhibit unprecedented estrogen receptor subtype selectivity [8–11]. …”