In the last decades, organometallic compounds have attracted increasing attention to investigate previously unattainable chemical transformations in biological environments. In fact, the incorporation of abiotic transition metal catalysts into the chemical biology space has significantly expanded the number of bioorthogonal reactions accessible for in vitro and in vivo applications. This is advantageous since catalytic metallodrugs could achieve high efficiency at low dosages and overcome cancer cells resistance through novel modes of actions. Similarly, such biorthogonal processes can be used to fight other bacterial and parasitic diseases. Thus, an increasing number of reports has appeared demonstrating that organometallic catalysts can operate under biological conditions, and even in living cells. In addition to redox processes and radical reactions, the chemistry of transition metal complexes has been rapidly expanding to other types of transformations in cells, including cross-coupling reactions, transfer hydrogenation (TH), cycloadditions, as well as functional group deprotection (uncaging) reactions.

In our group, we focus on cyclometalated Au(III) complexes able to template cross-coupling (C–S or C–Se) reactions with target proteins in biological environment, and more recently on Ru(II) mono-carbonyl complexes to catalyse TH of NAD⁺/NADH in cancer cells. Elucidation of the mechanisms of reactivity is conducted using different spectroscopic and analytical methods, as well as by XRD. Structure-activity relationships for the different families of organometallic compounds are also performed to tune and enhance selectivity. Of note, in addition to anticancer applications, the ‘catalytic’ metallodrugs are also envisaged as possible antibacterial and antiprotozoal agents. Finally, the integration of the gold chemistry into a proteolysis targeting chimera (PROTAC) concept is also ongoing. While on one side we will judiciously design the Gold-PROTACs to degrade selected oncoproteins and enzyme targets (e.g. thioredoxin reductase), a target-agnostic approach is also pursued, relying on a compound-centric view on all proteins addressed by a few “organogold-fragments” integrated into the PROTAC construct, elucidating their intrinsic selectivity and most relevant interactors by chemoproteomic/proteomic approaches. Compounds will be validated in human cancer cells selected according to the nature of the target.