A new class of phytoestrogens; evaluation of the estrogenic activity of deoxybenzoins.
Although deoxybenzoins are intermediates in the synthesis of isoflavones, their estrogenic activity has not been investigated. Eleven deoxybenzoins were synthesized and their estrogenicity was evaluated. While their affinities for estrogen receptors (ER) ERalpha and ERbeta were found grossly comparable to those of daidzein, some exhibited considerable selectivity and transcriptional bias toward ERbeta, which appeared to allow for enhancement of ER-mediated transcription via deoxybenzoin binding of ERbeta. Their activity to stimulate the proliferation of ER-positive breast cancer cells and regulate the expression of endogenous and stably transfected reporter genes differed considerably, with some inhibiting cell proliferation while effectively inducing gene expression at the same time. Molecular modeling confirmed that deoxybenzoins fit well in the ligand binding pocket of ERbeta, albeit with different orientations. Our data support the view that deoxybenzoins constitute a promising new class of ERbeta-biased phytoestrogens.
Fokialakis
Nikolas
N
Department of Pharmacy, University of Athens Panepistimiopolis Zografou, GR-15771 Athens, Greece.
Lambrinidis
George
G
Mitsiou
Dimitra J
DJ
Aligiannis
Nektarios
N
Mitakou
Sofia
S
Skaltsounis
Alexios-Leandros
AL
Pratsinis
Harris
H
Mikros
Emmanuel
E
Alexis
Michael N
MN
D000469:Alkaline Phosphatase / Q000378:metabolism; D001573:Benzoin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004958:Estradiol / Q000494:pharmacology; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D017930:Genes, Reporter / Q000235:genetics; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D008958:Models, Molecular; D008968:Molecular Conformation; D015394:Molecular Structure; D048789:Phytoestrogens; D028321:Plant Preparations / Q000138:chemical synthesis / Q000737:chemistry / Q000145:classification* / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000737:chemistry / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014158:Transcription, Genetic / Q000187:drug effects
D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D007529:Isoflavones; D048789:Phytoestrogens; D028321:Plant Preparations; D011960:Receptors, Estrogen; D004958:Estradiol; C004742:daidzein; D000469:Alkaline Phosphatase; C492807:deoxybenzoin; D001573:Benzoin