Diseño y síntesis de nuevos complejos de Ru(II) y Os(II) con potencial aplicación en quimioterapia y fototerapia del cáncer

Abstract

The aim of this Doctoral Thesis is the development of new ruthenium(II) and osmium(II) metallopharmaceuticals as potential agents for cancer treatment. The methodology employed is structured in three stages. Initially, the design, synthesis and characterization by different spectroscopic and spectrometric techniques of the new compounds are carried out. Then, their physicochemical properties and, where appropriate, their interaction with human serum albumin (HSA) are studied. Finally, the biological properties of the new compounds are studied. The manuscript has been structured in seven chapters, including Chapter I of introduction and Chapter VII of conclusions. In Chapter II, the objective was the development of new arene-complexes of cyclometallated Ru(II) and Os(II) as chemotherapeutic agents. The cyclometallated and the monodentate ligands have been modified and a structure-activity relationship (SAR) study has been performed. The compounds have been characterised and their stability in culture medium has been determined. In turn, the interaction with HSA has been studied, showing that the compounds with the 4-N,N-dimethylaminopyridine ligand interact more intensely. Moreover, these compounds are the most cytotoxic against tumour cell lines and the most selective, being less active against healthy cells. In addition, they can induce apoptosis in cancer cells due to disruption of the mitochondrial membrane potential and inhibition of protein synthesis. The best compounds have been studied in vivo in the animal model C. elegans. The complexes are able to reduce the gonad tumour size and increase lifespan. The aim of Chapter III is the development of new cyclometalated Ru(II) octahedral complexes as photosensitising agents in photodynamic therapy (PDT). A SAR study has been performed by modifying the π-conjugated system of the N^N ligands as well as the cyclometalated ligands. The compounds are stable in dark conditions and under visible light irradiation. Furthermore, they are able to catalytically photooxidise NADH and to photogenerate singlet oxygen. In addition, the complexes are cytotoxic in the dark, inhibiting protein synthesis, and are photoactivated under green light irradiation photogenerating reactive oxygen species. Furthermore, they maintain their activity under hypoxic conditions, making them good candidates as PDT agents. The main objective of Chapter IV is the development of new 2-(1-(aryl)-1,2,3-triazole-4-yl)benzothiazole compounds with different electronacceptor or electrondonor substituents. The compounds have been characterised and their optical properties have been studied, analysing the pull-push effect and solvatofluorochroism. Biological studies show that they are cytotoxic in tumor cell lines and are also selective. In Chapter V, the stablished objective is synthesize Ru(II) arene-complexes as antitumour agents, using the compounds obtained in Chapter IV as N^N chelate ligands. The compounds have been characterised and their optical properties and stability have been studied. The interaction with HSA has been analysed and different interaction intensities have been observed depending on the respective N^N ligand. The complexes are cytotoxic in cancer cell lines and less active against healthy cells. Finally, the aim of Chapter VI is the synthesis of octahedral Ru(II) complexes [Ru(phen)2(N^N)](OTf)2 as prodrugs for photoactivated chemotherapy (PACT), using the N^N ligands obtained in Chapter IV. The complexes have been characterised and their photochemical properties have been studied, showing that they are stable in the dark, conditions in which they are not cytotoxic, but when irradiated with blue light they photoliberate the ligand 2-(1-(aryl)-1,2,3-triazole-4-yl)benzothiazole and induce cytotoxicity. They are good candidates as prodrugs for PACT.