Novel antitumor copper(ii) complexes designed to act through synergistic mechanisms of action, due to the presence of an NMDA receptor ligand and copper in the same chemical entity. (21st June 2018)

• Record Type: Journal Article
• Authors: Morelli, Maria Beatrice; Amantini, Consuelo; Santoni, Giorgio; Pellei, Maura; Santini, Carlo; Cimarelli, Cristina; Marcantoni, Enrico; Petrini, Marino; Del Bello, Fabio; Giorgioni, Gianfabio; Piergentili, Alessandro; Quaglia, Wilma
• Is Part Of: New journal of chemistry. Volume 42:Number 14(2018)
• Page Start: 11878
• Page End: 11887
• Publication Date: 2018-06-21
• Subjects: Chemistry -- Periodicals; Chimie -- Périodiques; 540
• DOI: 10.1039/c8nj01763h
• Languages: English
• ISSNs: 1144-0546

Abstract

Abstract : An NMDA receptor ligand was linked to bifunctionalizable species to form copper(ii ) complexes, showing antitumor activity through synergistic action mechanisms. Abstract : In the present article the 1, 4-dioxane derivative1, a potent noncompetitive NMDA receptor antagonist, showed cytotoxic activity in the MCF7 breast cancer cell line significantly higher than those of the functionally related compounds ( S )-(+)-ketamine and MK-801. Encouraged by this result and considering that copper complexes have been highlighted to be promising anticancer agents, the NMDA receptor ligand1 was linked to the bifunctionalizable species2 and3, affording the conjugated derivatives4 and5 that were used for the preparation of the stable Cu(ii ) complexes6 and7 . All the compounds were evaluated against a panel of human cancer cell lines derived from solid tumors. Complex7 showed the best antitumor activity in all the studied cell lines. This result suggests that7 might act through synergistic mechanisms of action due to the presence of the NMDA ligand1 and copper(ii ) in the same chemical entity. Furthermore, the cellular mechanisms affected by complex7 were assessed through cytofluorimetric and western blot analyses. Data suggested the induction of cell death through paraptosis mediated by endoplasmic reticulum (ER) stress.