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Identification of two benzopyrroloxazines acting as selective GPER antagonists in breast cancer cells and cancer-associated fibroblasts

    Marcello Maggiolini

    Department of Pharmacy, Health & Nutritional Sciences, University of Calabria, via P Bucci, 87036 Rende (Cs), Italy

    Authors contributed equally

    Search for more papers by this author

    ,
    Maria Francesca Santolla

    Department of Pharmacy, Health & Nutritional Sciences, University of Calabria, via P Bucci, 87036 Rende (Cs), Italy

    ,
    Silvia Avino

    Department of Pharmacy, Health & Nutritional Sciences, University of Calabria, via P Bucci, 87036 Rende (Cs), Italy

    ,
    Francesca Aiello

    Department of Pharmacy, Health & Nutritional Sciences, University of Calabria, via P Bucci, 87036 Rende (Cs), Italy

    ,
    Camillo Rosano

    U.O.S.Biopolymers and Proteomics, IRCCS A.O.U. San Martino – IST, National Institute for Cancer Research, Largo R. Benzi 10, 16132 Genova, Italy.

    ,
    Antonio Garofalo

    Department of Pharmacy, Health & Nutritional Sciences, University of Calabria, via P Bucci, 87036 Rende (Cs), Italy

    &
    Fedora Grande,‡

    *Author for correspondence:

    E-mail Address: fedora.grande@unical.it

    Department of Pharmacy, Health & Nutritional Sciences, University of Calabria, via P Bucci, 87036 Rende (Cs), Italy

    Authors contributed equally

    Search for more papers by this author

    Published Online:https://doi.org/10.4155/fmc.15.3

    Background: G-protein coupled estrogen receptor (GPER) is involved in numerous intracellular physiological and pathological events including cancer cell migration and proliferation. Its characterization is yet incomplete due to the limited number of specific ligands. Results: Two novel selective GPER antagonists, based on a benzo[b]pyrrolo[1,2-d][1,4]oxazin-4-one structure, have been designed and synthesized. Their binding to the receptor was confirmed by a competition assay, while the antagonist effects were ascertained by their capability to prevent the ligand-stimulated action of GPER. The transcription mediated by the classical estrogen receptor was not influenced, demonstrating selectivity for GPER. Conclusion: These novel compounds may be considered useful leads toward the dissection of the GPER signaling and the development of new pharmacological treatments in breast cancer.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

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