Novel BODIPY-estradiol conjugates have been synthesized by selecting position C-3-O for labeling. The conjugation strategy was based on Cu(I)-catalyzed azide-alkyne cycloaddition (CuAAC) or etherification. Estradiol derivatives used as azide partners bearing an ω-azidoalkyl function through C4-C8-long linkers have been prepared. CuAAC reactions of estradiol azides with BODIPY alkyne furnished fluorescent 3-O-labeled conjugates bearing the triazole ring as a coupling moiety. Williamson etherifications of 3-O-(ω-bromoalkyl)-17β-estradiol derivatives with BODIPY-OH resulted in labeled conjugates connected with an ether moiety. Interactions of the conjugates with estrogen receptor (ER) were investigated using molecular docking calculations in comparison with estradiol. The conjugates occupied both the classical and alternative binding sites on human ERα, with slightly lower binding affinity to references estradiol and diethystilbestrol. All compounds have displayed reasonable estrogenic activity. They increased the proliferation of ER-positive breast cancer cell line MCF7 contrary to ER-negative SKBR-3 cell line. The most potent compound 13a induced the transcriptional activity of ER in dose-dependent manner in dual luciferase recombinant reporter model and increased progesterone receptor's expression, proving the retained estrogenic activity. The fluorescence of candidate compound 13a co-localised with the ERα. The newly synthesized labeled compounds might serve as good starting point for further development of fluorescent probes for modern biological applications. In addition to studying steroid uptake and transport in cells, e.g. in the processes of biodegradation of estrogen-hormones micropollutants, they could also be utilized in examination of estrogen-binding proteins.

Department of Experimental Biology Faculty of Science Palacký University Olomouc Šlechtitelů 27 78371 Olomouc Czech Republic

Department of Inorganic Organic and Analytical Chemistry University of Szeged Dóm tér 7‒8 H 6720 Szeged Hungary

Department of Inorganic Organic and Analytical Chemistry University of Szeged Dóm tér 7‒8 H 6720 Szeged Hungary; Department of Pharmacognosy University of Szeged Eötvös u 6 H 6720 Szeged Hungary

Department of Laboratory Medicine Medical School University of Pécs Ifjúság útja 13 Pécs H 7624 Hungary; Molecular Medicine Research Group János Szentágothai Research Centre University of Pécs Ifjúság útja 20 Pécs H 7624 Hungary

Department of Organic Chemistry University of Debrecen Egyetem tér 1 H 4032 Debrecen Hungary

Department of Pharmacology and Pharmacotherapy Medical School University of Pécs Szigeti út 12 H 7624 Pécs Hungary

Drug resistance research group Institute of Enzymology Research Centre for Natural Sciences Magyar tudósok körútja 2 H 1117 Budapest Hungary

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