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
  • 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.