2. Academic Validation
  3. Role of the NMDA Receptor in the Antitumor Activity of Chiral 1,4-Dioxane Ligands in MCF-7 and SKBR3 Breast Cancer Cells

Role of the NMDA Receptor in the Antitumor Activity of Chiral 1,4-Dioxane Ligands in MCF-7 and SKBR3 Breast Cancer Cells

  • ACS Med Chem Lett. 2019 Jan 28;10(4):511-516. doi: 10.1021/acsmedchemlett.8b00536.
Maria Beatrice Morelli 1 2,  Consuelo Amantini 1,  Massimo Nabissi 2,  Giorgio Santoni 2,  Bernhard Wünsch 3,  Dirk Schepmann 3,  Cristina Cimarelli 4,  Maura Pellei 4,  Carlo Santini 4,  Stefano Fontana 5,  Valerio Mammoli 5,  Wilma Quaglia 6,  Alessandro Bonifazi 6,  Mario Giannella 6,  Gianfabio Giorgioni 6,  Alessandro Piergentili 6,  Fabio Del Bello 6
Affiliations

Affiliations

  • 1 School of Biosciences and Veterinary Medicine, University of Camerino, via Madonna delle Carceri 9, 62032 Camerino, Italy.
  • 2 School of Pharmacy, Immunopathology Unit, University of Camerino, via Madonna delle Carceri 9, 62032 Camerino, Italy.
  • 3 Institut für Pharmazeutische und Medizinische Chemie, Universität Münster, Corrensstraße 48, 48149 Münster, Germany.
  • 4 School of Science and Technology, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.
  • 5 Center for Drug Discovery and Development-DMPK, Aptuit, an Evotec Company, via A. Fleming 4, 37135 Verona, Italy.
  • 6 School of Pharmacy, Medicinal Chemistry Unit, University of Camerino, via S. Agostino 1, 62032 Camerino, Italy.
PMID: 30996788 DOI: 10.1021/acsmedchemlett.8b00536
Abstract

The potent N-methyl-d-aspartate (NMDA) receptor antagonists 1-3 have been demonstrated to show antiproliferative and cytotoxic effects in MCF-7 and SKBR3 breast Cancer cell lines. To improve the knowledge about the role played by the NMDA Receptor in the antitumor activity of these compounds, the enantiomers of 1 were prepared and evaluated for their affinity for the phencyclidine (PCP) site of the NMDA Receptor and for their cytotoxic effect in MCF-7 and SKBR3 cell lines, both expressing the NMDA Receptor. The (S)-1 enantiomer, showing negligible affinity for the PCP site, exhibited antiproliferative activity higher than that of (R)-1, which instead bound the PCP site. The downregulation of NMDA GluN1 expression resulted in a decreased (S)-1-induced cytotoxicity and apoptotic cell death, unequivocally demonstrating the involvement of the NMDA Receptor in the antitumor effect of this compound. Due to its interesting biological profile, (S)-1 represents a lead compound to develop novel antitumor agents for breast Cancer treatment.

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