Exploiting MS-based techniques to unveil elusive reaction intermediates of bioinorganic relevance

The periodic table for a medicinal chemist or a biochemist is usually restricted to very few elements. More than 95% of the mass of living systems is indeed composed by carbon, hydrogen, nitrogen and oxygen. Besides, elements present only in trace amount can have irreplaceable roles in the chemistry of life. Even more surprisingly, transition metals completely unrelated to living systems have found their way in therapy and, nowadays, antineoplastic drugs containing for example platinum are widespread. However, many techniques routinely exploited for analyzing chemical reactions in solution fail to characterize the properties of metal complexes, in particular in their interaction with biological molecules. The aim of this thesis is to show how electrospray ionization (ESI) mass spectrometry (MS) may excel in capturing elusive species from solution. One can thus shed light on reaction mechanisms of biological relevance and gain insight about coordination sites of biomolecules in binding metals. This work is focusessed on platinum complexes moving from the PtII-containing anticancer drug cisplatin to novel PtIV complexes, which are promising candidates to be at the forefront of future platinum-based therapies. To obtain structural insights about the species of interest, several MS-based techniques have been exploited. IR multiple photon dissociation (IRMPD) spectroscopy was used to obtain the vibrational features of mass selected species. IRMPD spectroscopy combined with calculations at the DFT level, to interpret the experimental vibrational features, allowed us to tackle a variety of issues. Among them, we could unveil the nature of the encounter complex lying on the reaction coordinate of ligand exchange of cisplatin with model biological targets. IRMPD spectroscopy was also employed to characterize the primary intermediates formed by cisplatin reacting with histidine and methionine, major platination targets in proteins. Eventually, IRMPD kinetics on isomer- and conformer-specific vibrational modes were also used to obtain semi-quantitative information about the conformational landscape of cisplatin derived complexes. Collision induced dissociation (CID) was instead the MS/MS technique of choice to gain information about the gas-phase reactivity of platinum(IV) complexes. Using high-resolution mass spectrometry a complete fragmentation pattern was achieved by assigning an unambiguous molecular formula and so characterizing exotic species generated by reduction of PtIV.