Beyond Metal-Arenes: Monocarbonyl Ruthenium(II) Catalysts for Transfer Hydrogenation Reactions in Water and in Cells

With the aim to design water-soluble organometallic Ru(II)complexesacting as anticancer agents catalyzing transfer hydrogenation (TH)reactions with biomolecules, we have synthesized four Ru(II) monocarbonylcomplexes (1-4), featuring the 1,4-bis(diphenylphosphino)butane(dppb) ligand and different bidentate nitrogen ((NN)-N-& BOTTOM;) ligands, of general formula [Ru(OAc)CO(dppb)((NN)-N-& BOTTOM;)] (n) (n = +1, 0; OAc= acetate). The compounds have been characterized by different methods,including H-1 and P-31 NMR spectroscopies, electrochemistry,as well as single-crystal X-ray diffraction in the case of 1 and 4. The compounds have also been studied for theirhydrolysis in an aqueous environment and for the catalytic regioselectivereduction of nicotinamide adenine dinucleotide (NAD(+)) to1,4-dihydronicotinamide adenine dinucleotide (1,4-NADH) in aqueoussolution with sodium formate as a hydride source. Moreover, the stoichiometricand catalytic oxidation of 1,4-NADH have also been investigated byUV-visible spectrophotometry and NMR spectroscopy. The resultssuggest that the catalytic cycle can start directly from the intactRu(II) compound or from its aquo/hydroxo species (in the case of 1-3) to afford the hydride ruthenium complex.Overall, initial structure-activity relationships could beinferred which point toward the influence of the extension of thearomatic (NN)-N-& BOTTOM; ligand in the cationic complexes 1-3 on TH in both reduction/oxidationprocesses. While complex 3 is the most active in TH fromNADH to O-2, the neutral complex 4, featuringa picolinamidate (NN)-N-& BOTTOM; ligand, stands out as the mostactive catalyst for the reduction of NAD(+), while beingcompletely inactive toward NADH oxidation. The compound can also convertpyruvate into lactate in the presence of formate, albeit with scarceefficiency. In any case, for all compounds, Ru(II) hydride intermediatescould be observed and even isolated in the case of complexes 1-3. Together, insights from the kineticand electrochemical characterization suggest that, in the case ofRu(II) complexes 1-3, catalytic NADHoxidation sees the H-transfer from 1,4-NADH as the rate-limiting step,whereas for NAD(+) hydrogenation with formate as the H-donor,the rate-limiting step is the transfer of the ruthenium hydride tothe NAD(+) substrate, as also suggested by density functionaltheory (DFT) calculations. Compound 4, stable with respectto hydrolysis in aqueous solution, appears to operate via a differentmechanism with respect to the other derivatives. Finally, the anticanceractivity and ability to form reactive oxygen species (ROS) of complexes 1-3 have been studied in cancerous andnontumorigenic cells in vitro. Noteworthy, the conversionof aldehydes to alcohols could be achieved by the three Ru(II) catalystsin living cells, as assessed by fluorescence microscopy. Furthermore,the formation of Ru(II) hydride intermediate upon treatment of cancercell extracts with complex 3 has been detected by H-1 NMR spectroscopy. Overall, this study paves the way to theapplication of non-arene-based organometallic complexes as TH catalystsin a biological environment.