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Metallodrugs to Modulate Tumour Cell Machinery

Final Report Summary - MEMOTUMCELLMACH (Metallodrugs to Modulate Tumour Cell Machinery)

The general aim of this proposal is to create pH-responsive metalloorganic molecular switches capable of activation towards biomolecule interaction within cells in a pH-dependent manner. To this end, we have developed switches based on ruthenium(II), osmium(II) and iridium(III).
The ruthenium sub-project has pioneered the establishment of the switchable system. In a general structure [Ru(eta6,kappa1-arene,N/O)(L^L’)]Cl2 (where L^L’ is a chelating ligand), changes in the different ligands around the metal have led to an understanding of which electronic and steric features of the different building blocks can help tailor the pH of activation. Most importantly, our design allows for deactivation upon drop in the proton concentration (increase in the pH). The dynamics of the switch have been carefully studied and have allowed us to conclude that the rates at which both processes (activation and deactivation) occur are also pH dependent. Osmium analogues have been isolated and their dynamics in aqueous solution thoroughly investigated. The osmium-arene compounds have opened up the possibility of creating intracellular proton shuttles. The iridium sub-project has also produced striking results, with cytotoxic activities in the nanomolar range, targeting capabilities at the intracellular level only matched by tagged molecules, and activation processes that hint at intracellular catalytic events.
The grant has greatly contributed to the consolidation of the fellow (Dr Pizarro) and enable her to start her own research line, creating her group at the host institution, and to the establishment of new national and international collaborations.