New copper(I) and copper(I)-ruthenium(II) complexes promising for cancer therapy

Authors and Affiliations:

João Lopes^a,c, David Alves^a,c, Tânia S. Morais^a,b,c, Paulo J. Costa^c,d, M. Fátima M. Piedade^c,e, Fernanda Marques^f, Maria J. Villa de Brito^a,c, M. Helena Garcia^a,c

^a Centro de Química Estrutural, Faculdade de Ciências, Universidade de Lisboa, Portugal

^b Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Portugal

^c Departamento de Química e Bioquímica, Faculdade de Ciências, Universidade de Lisboa, Portugal

^d Centro de Química e Bioquímica, DQB, Faculdade de Ciências, Universidade de Lisboa, Portugal

^e Centro de Química Estrutural, Instituto Superior Técnico, Universidade de Lisboa, Portugal

^f Centro de Ciências e Tecnologias Nucleares, Instituto Superior Técnico, Universidade de Lisboa, Portugal

Abstract:

A new family of copper(I) complexes of general formula [Cu(dppe)(NN)]⁺ have been synthesized and fully characterized, with dppe = 1.2-bis(diphenylphosphino)ethane and NN representing several bidentate heteroaromatic ligands: 2,2′-bipy = 2.2′-bipyridine (1), Me₂bpy = 4.4′-dimethyl-2,2′-bipyridine (2), dpytz = 3-(2-pyridyl)-5,6-diphenyl-1,2,4-triazine (3), dpp = 2.3-bis(2-pyridyl)pyrazine (4), and the metallaligand [Ru(η⁵-C₅H₅)(PPh₃)(dpp)]⁺ (5), yielding the bimetallic copper(I)-ruthenium(II) complex [Cu(dppe)(μ-dpp)Ru(η⁵-C₅H₅)(PPh₃)]₂ ⁺ (6). The single crystal structures of complexes (2) and (4) were determined by X-ray diffraction studies. All the complexes exhibit high cytotoxicity against the human cancer cells A2780 and MCF7 with IC₅₀ values far lower than those found for the antitumor drug cisplatin in the same cell lines and even surpassing cisplatin resistance in the A2780cisR cells. They display IC₅₀ values on the human embryonic kidney HEK293 non-tumoral cells of the same order of magnitude as those found for the tumoral cells. In the ovarian cells the compounds induce rapid production of reactive oxygen species (ROS) probably through mitochondrial pathways. According to the results reported here, these compounds can be considered as prospective antitumoral agents that deserve further evaluation.

Journal: Journal of Inorganic Biochemistry

Link: http://www.sciencedirect.com/science/article/pii/S0162013417300260