Synthesis and Evaluation of Estrogen Agonism of Diaryl 4,5-Dihydroisoxazoles, 3-Hydroxyketones, 3-Methoxyketones, and 1,3-Diketones: A Compound Set Forming a 4D Molecular Library

Abstract

In this paper, the preparation and systematic evaluation of estrogen receptor alpha (ER alpha) and estrogen receptor beta (ER beta) activities of some diaryl-1,3-diones and their synthetic intermediates, diaryl-4,5-dihydroisoxazoles, diaryl-3-hydroxyketones, diaryl-3-methoxyketones, and diaryl-2-(dimethyl-lambda 4-sulfanylidene)-1,3-diones, is described. The set of 72 compounds constitutes a general schematic structure aryl1-linker1-spacer-linker2-aryl2, where the linker1-spacer-linker2 length varies between 4 and 8 carbons. The set of compounds was applied here to map and explore the active sites of subtypes ER alpha and ER beta. The highest activities were obtained with dihydroisoxazole and hydroxyketone spacers, but even the most flexible diones with unsubstituted aryl groups showed some agonism. Most compounds were found to be ER alpha selective or to activate both receptors, but in some cases we saw also clearly stronger ER beta activation.

Synthesis and biological evaluation of phenolic 4,5-dihydroisoxazoles and 3-hydroxy ketones as estrogen receptor α and β agonists

“…23,24 The dipolar cycloaddition reaction leads to 4,5-dihydroisoxazoles C, the aromatic methoxy groups of which can be demethylated by BBr 3 to produce the phenol function of the compounds D. Finally, the phenolic isoxazoles D were converted to corresponding hydroxy ketones E by catalytic hydrogenation and hydrolysation with Raney Ni in the presence of H 2 O and AcOH. After preparation, all compounds were run through semi-preparative HPLC system 23 and, with one exception, we were able to separate all the enantiomers of compounds D (Tables 1 and 2). Neither specific rotation nor absolute configuration was resolved due to the small amounts of the purified enantiomers.…”

“…23,26 The reporter activities of the test compounds (10 lM) were normalized to the activation observed for 10 nM E2 (= 100), and the specificity activation was ascertained by transfections lacking ERs and inclusion of the ER antagonist ICI-182,780. 23 The relative ER binding affinities (RBA, Table 3) were determined by a competitive assay against [6, H(N)]estradiol in COS-1 cells using a wide range of concentrations to determine each chemical's EC 50 and relative binding affinity (RBA) values as compared to E2 (= 100%).…”

“…23,26 The reporter activities of the test compounds (10 lM) were normalized to the activation observed for 10 nM E2 (= 100), and the specificity activation was ascertained by transfections lacking ERs and inclusion of the ER antagonist ICI-182,780. 23 The relative ER binding affinities (RBA, Table 3) were determined by a competitive assay against [6, H(N)]estradiol in COS-1 cells using a wide range of concentrations to determine each chemical's EC 50 and relative binding affinity (RBA) values as compared to E2 (= 100%). 27 Overall, the phenolic hydroxyl group as R 1 substituent (Aryl 1, see Tables 1 and 2 for the structures) is a structural feature important for the affinity of the ligands and in comparison to unsubstituted analogs, compounds with a phenolic Aryl 1 have both higher receptor activities and RBAs.…”

“…Recently, we reported novel estrogen agonists, which have a core structure consisting of a spacer and flexible linkers between the spacer and the aryl groups. 23 The spacers have chiral sp 3 -centres and varying lengths of the CH 2 -linker provide a distance of 4-8 carbons between the aromatic rings. The in vitro studies showed that the best estrogen agonists had a 4,5-dihydroisoxazole or 3-hydroxyketone moiety as the spacer.…”

Understanding the Regioselective and Molecular Mechanism of the TCE in Cycloaddtion Reaction (TCE+Cp) and Addition Reaction (TCE+HCl) using DFT calculation

“…They are also useful intermediates for synthesis of natural products and biologically active compounds [4][5][6][7][8][9][10]. A variety of synthetic methods has been developed for preparation of cyclic compounds, of which the most convenient and attractive route is probably the cycloaddition of diene or dipole to alkenes [10][11].…”