Bioorthogonal Catalysts for the Reduction of Aldehydes by Transfer Hydrogenation



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Bioorthogonal reactions catalyzed by inorganic complexes have useful applications in biology and medicine. These reactions could be used to mediate bioconjugations of fluorescent dyes to proteins, convert non-toxic precursor molecules to biologically active compounds, or neutralize chemical toxins to non-hazardous substances. Because of the heterogeneous nature of biological environments, developing catalysts that can operate inside living cells is challenging. To expand the biocompatible reaction toolbox, we investigated intracellular transfer hydrogenation reactions catalyzed by organometallic iridium catalysts. Formation of hydrogenation products in cells was visualized by fluorescence microscopy using a fluorogenic bodipy substrate. No fluorescence was observed in cells that were not treated with iridium catalyst. We propose that the reduced cofactor nicotinamide adenine dinucleotide (NADH) is a possible hydride source inside the cell based on studies using pyruvate as a cellular redox modulator. To quantify the transfer hydrogenation efficiency in cells, we used liquid chromatography-mass spectrometry to measure the yield of alcohol products generated in live cell experiments. Differences in the intracellular activity of the catalysts were explained by the differences in their toxicity and cellular uptake. Additionally, we have synthesized a series of fluorogenic iridium catalysts to study the spatial distribution of the catalysts inside cells. We also describe our efforts to prepare biocompatible transfer hydrogenation catalysts based on cobalt rather than iridium. Finally, we also present our work on developing off-on fluorescent probes to quantify transfer hydrogenation reactions in live cells. Some of the challenges that we encountered include poor substrate reactivity even in the reaction flask, poor cellular uptake and cell retention of the substrate and the product. This work is the first ever example of aldehyde reduction by iridium catalysts in live cells. We also showed that poor efficiency of iridium catalysts in live cells is related to their toxicity and cellular uptake. The detailed study on catalyst activity in live cells will help researchers modifying the ligands accordingly to achieve higher intracellular efficiency. This new type of bioorthogonal chemistry could be used as a new therapeutic tool in future to treat aldehyde toxicity.



Catalysts, Hydrogenation


Portions of this document appear in: Ngo, Anh H., Sohini Bose, and Loi H. Do. "Intracellular chemistry: integrating molecular inorganic catalysts with living systems." Chemistry–A European Journal 24, no. 42 (2018): 10584-10594. And in: Bose, Sohini, Anh H. Ngo, and Loi H. Do. "Intracellular transfer hydrogenation mediated by unprotected organoiridium catalysts." Journal of the American Chemical Society 139, no. 26 (2017): 8792-8795.