Organometallic Complexes in Biological Applications: Synthesis, Mechanism, and In Vitro Behavior

Transition metal complexes are attractive as bioactive compounds due to their structural complexity and ability to achieve high potency and selectivity. In recent years, the development of these complexes has gained much popularity due to their synthetically accessibility and tunable reactivity. However, creating complexes that are non-toxic and active inside biological environments is highly challenging. Herein, we describe the synthesis of new organometallic complexes and their possible application as anti-cancer agents. In the first project, a bifunctional complex featuring a quinone and picolinamide iridium moieties was synthesized as new transfer hydrogenation catalysts. We proposed that this catalyst design would enable more efficient generation of hydrogen peroxide by taking advantages of intramolecular reactivity. In the presence of sodium formate, our catalytic produced more hydrogen peroxide compared to that by the corresponding tandem catalysts under physiological conditions. We characterized several key reaction intermediates by VT NMR spectroscopy and determined catalyst stability over time. The biocompatibility of the complex toward cancer cell lines was also evaluated. The second project was performed in collaboration with Dr. Michihisa Umetani, in which we attempted to develop synthetic liver X receptor agonists (GW3965) that are nucleus impermeable and can selectively inhibit nuclear gene expression. Toward this goal, we covalently attached GW3965 to ruthenium/rhodium/iridium complexes using a variety of linkers. The fluorescent cyclometalated iridium complex bearing two GW3965 units showed extra-nuclear localization via live cell imaging. The distribution of Ru/Rh compounds is currently being investigated by Inductive coupled plasma-mass spectroscopy (ICP-MS). Further studies using qPCR, cell proliferation, and cytotoxicity assays would be conducted evaluate these complexes’ behavior inside cells. Our work had led to the first demonstration of using intramolecular transfer hydrogenation to enhance H2O2 generation at low catalyst concentrations. We also introduced a new approach for reducing the nuclear permeability of Liver X Receptor agonists. We believe the insights gained from the studies could be used to develop more biocompatible systems in the future.