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.
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.
Laboratories of Chemistry, Biochemistry, Department of Biosciences, University of Kuopio, PO Box 1627, FIN-70211 Kuopio, Finland. juha.pulkkinen@uku.fi
Juha T
JT
Pulkkinen
Paavo
P
Honkakoski
Mikael
M
Peräkylä
Istvan
I
Berczi
Reino
R
Laatikainen
D001665:Binding Sites; D002460:Cell Line; D047628:Estrogen Receptor alpha / Q000819:agonists* / Q000235:genetics; D047629:Estrogen Receptor beta / Q000819:agonists* / Q000235:genetics; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007659:Ketones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008024:Ligands; D008958:Models, Molecular; D054852:Small Molecule Libraries; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007555:Isoxazoles; D007659:Ketones; D008024:Ligands; D054852:Small Molecule Libraries