Anti-proliferative effects of copper(II) complexes with hydroxyquinoline-thiosemicarbazone ligands.
The possibility to influence the physiological concentration of copper ions through the careful choice of ligands is emerging as a novel intriguing strategy in the treatment of pathologies such as cancer and Alzheimer. Thiosemicarbazones play an important role in this field, because they offer a wide variety of potential functionalizations and different kinds of coordination modes. Here we report the synthesis of some 8-hydroxyquinoline thiosemicarbazone ligands containing an ONN'S donor set and their Zn(II) and Cu(II) complexes. The metal complexes were characterized in solution and in the solid state and the X-ray structure of one of the copper(II) complex is reported. The Cu(II) complexes were characterized also by means of quantum mechanical calculations. The Cu(II) complexes displayed cytostatic activity in different cancer cell models. In particular, the most active Cu(II) complex significantly inhibited cell proliferation with an IC50value lower than 1 μM; this effect was associated with a block of the cell cycle in the G2/M phase. This Cu(II) complex induced neither the production of reactive oxygen species (ROS) nor the accumulation of p53 protein, suggesting the lack of DNA damage.
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy. Electronic address: dominga.rogolino@unipr.it.
Dominga
D
Rogolino
Department of Clinical and Experimental Medicine, University of Parma, Italy.
Andrea
A
Cavazzoni
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
Anna
A
Gatti
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
Matteo
M
Tegoni
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
Giorgio
G
Pelosi
Department of Chemistry and Applied Biosciences, Eidgenössusche Technische Hochschule Zürich, CH-8093 Zurich, Switzerland; Facoltà di Informatica, Istituto di Scienze Computazionali, Università della Svizzera Italiana, 6900 Lugano, Ticino, Switzerland.
Vincenzo
V
Verdolino
Department of Clinical and Experimental Medicine, University of Parma, Italy.
Claudia
C
Fumarola
Department of Clinical and Experimental Medicine, University of Parma, Italy.
Daniele
D
Cretella
Department of Clinical and Experimental Medicine, University of Parma, Italy.
Pier Giorgio
PG
Petronini
Dipartimento di Scienze Chimiche, della Vita e della Sostenibilità Ambientale and Consorzio Interuniversitario di Ricerca in Chimica dei Metalli nei Sistemi Biologici, Università di Parma, Parco Area delle Scienze 17/A, 43124 Parma, Italy.
Mauro
M
Carcelli
D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D056831:Coordination Complexes / Q000737:chemistry*; D003300:Copper / Q000737:chemistry*; D018360:Crystallography, X-Ray; D006801:Humans; D006912:Hydroxyquinolines / Q000737:chemistry*; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013882:Thiosemicarbazones / Q000737:chemistry*
D000970:Antineoplastic Agents; D056831:Coordination Complexes; D006912:Hydroxyquinolines; D008024:Ligands; D017382:Reactive Oxygen Species; D013882:Thiosemicarbazones; D003300:Copper
8-Hydroxyquinoline; Anticancer; Copper(II) complex; Proliferation; ROS; Thiosemicarbazone