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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

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posted on 26.06.2008, 00:00 by Juha T. Pulkkinen, Paavo Honkakoski, Mikael Peräkylä, Istvan Berczi, Reino Laatikainen
In this paper, the preparation and systematic evaluation of estrogen receptor α (ERα) and estrogen receptor β (ERβ) 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-λ4-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 ERα and ERβ. 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 ERα selective or to activate both receptors, but in some cases we saw also clearly stronger ERβ activation.