Speaker
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Cancer remains one of the leading causes of mortality worldwide, and the emergence of resistance to conventional chemotherapeutic agents continues to represent a major challenge in oncology.$^1$ The investigation of transition metal-based cytotoxic compounds capable of overcoming this limitation has therefore become a critical point in contemporary bioinorganic chemistry. In this context, we have previously reported that RAPTA-type complexes, in which a ruthenium center is bridged to a secondary metal unit through a bidentate ligand, exhibit enhanced selectivity toward multiple cancer cells lines as a consequence of synergistic interactions between two metal centers.$^2$ The PTA-derived ligand dmoPTA (3,7-dimethyl-1,3,7-triaza-5-phosphabicyclo[3.3.1]nonane) is able to chelate an additional metal center,$^3$$^,$$^4$ giving rise to the most active heterometallic species synthesized to date by us, with IC$_5$$_0$ values in the range of 20-41 nM.$^5$
Building upon these findings, in order to advance the design of novel complexes exhibiting notable antiproliferative properties and to understand their underlying mechanisms of action, we have developed a new series of monometallic precursor complexes as starting points for subsequent heterodimetallic complexes with enhanced cytotoxic activity, and also a new generation of novel heterotrimetallic complexes. Their antiproliferative properties were studied against colon cancer cell line Caco-2/TC7, showing that their cytotoxic activity can be tuned by halogen variation motivated by the different interaction with water molecules. Therefore, light can be shed on their behavior if interaction between water and complexes is determined by neutron scattering experiments on their aqueous solutions and in presence of DNA.
Keywords: Ruthenium, Halogen, Zinc, PTA derivatives, RAPTA, Heterometallic complexes, Antiproliferative activity, Neutron scattering.
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