Anticancer Activity of Half-Sandwich Ru, Rh and Ir Complexes with Chrysin Derived Ligands: Strong Effect of the Side Chain in the Ligand and Influence of the Metal
Ana R. Rubio,
Rocío González,
Natalia Busto,
Mónica Vaquero,
Ana L. Iglesias,
Félix A. Jalón,
Gustavo Espino,
Ana M. Rodríguez,
Begoña García,
Blanca R. Manzano
Affiliations
Ana R. Rubio
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Rocío González
Facultad de Ciencias y Tecnologías Químicas-IRICA, Universidad de Castilla-La Mancha, Avda. C. J. Cela 10, 13071 Ciudad Real, Spain
Natalia Busto
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Mónica Vaquero
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Ana L. Iglesias
Facultad de Ciencias y Tecnologías Químicas-IRICA, Universidad de Castilla-La Mancha, Avda. C. J. Cela 10, 13071 Ciudad Real, Spain
Félix A. Jalón
Facultad de Ciencias y Tecnologías Químicas-IRICA, Universidad de Castilla-La Mancha, Avda. C. J. Cela 10, 13071 Ciudad Real, Spain
Gustavo Espino
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Ana M. Rodríguez
Departamento de Química Inorgánica, Orgánica y Bioquímica, Escuela Técnica Superior de Ingenieros Industriales, Universidad de Castilla-La Mancha, Avda. C. J. Cela 2, 13071 Ciudad Real, Spain
Begoña García
Departamento de Química, Facultad de Ciencias, Universidad de Burgos, Plaza Misael Bañuelos s/n, 09001 Burgos, Spain
Blanca R. Manzano
Facultad de Ciencias y Tecnologías Químicas-IRICA, Universidad de Castilla-La Mancha, Avda. C. J. Cela 10, 13071 Ciudad Real, Spain
An important challenge in the field of anticancer chemotherapy is the search for new species to overcome the resistance of standard drugs. An interesting approach is to link bioactive ligands to metal fragments. In this work, we have synthesized a set of p-cymene-Ru or cyclopentadienyl-M (M = Rh, Ir) complexes with four chrysin-derived pro-ligands with different -OR substituents at position 7 of ring A. The introduction of a piperidine ring on chrysin led to the highly cytotoxic pro-ligand HL4 and its metal complexes L4-M (SW480 and A549 cell lines, cytotoxic order: L4-Ir > L4-Ru ≈ L4-Rh). HL4 and its complexes induce apoptosis and can overcome cis-platinum resistance. However, HL4 turns out to be more cytotoxic in healthy than in tumor cells in contrast to its metal complexes which displayed higher selectivity than cisplatin towards cancer cells. All L4-M complexes interact with double stranded DNA. Nonetheless, the influence of the metal is clear because only complex L4-Ir causes DNA cleavage, through the generation of highly reactive oxygen species (1O2). This result supports the hypothesis of a potential dual mechanism consisting of two different chemical pathways: DNA binding and ROS generation. This behavior provides this complex with a great effectivity in terms of cytotoxicity.
