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Acetoxymethyl (AM) Concept for Intracellular Administration of Carbon Monoxide with Mn(CO)3-Based photoCORMs

Mede, Ralf; Hoffmann, Patrick; Neumann, Clara; Görls, Helmar; Schmitt, Michael; Popp, Jürgen; Neugebauer, Ute; Westerhausen, Matthias
in: Chemistry-A European Journal (2018) 3321

Targeted administration of carbon monoxide with CO releasing molecules (CORMs) inside of cells proved to be very challenging. Consequently, there are only very few reports on intracellular uptake of CORMs requiring high extracellular CORM loading because an equilibrium between extra- and intracellular concentrations can be assumed. Here we present a strategy for a targeted intracellular administration of manganese (I)-based CORMs that are altered inside of cells to trap these complexes. Thereafter, carbon monoxide can be liberated by irradiation (photo CORMs). To achieve this innovative task, acetoxymethyl (AM) groups are attached at the periphery of the hydrophobic manganese (I) carbonyl complexes to not influence the CO release behavior. Inside of cells these AM substituents are cleaved by esterases yielding hydrophilic manganese (I) carbonyl compounds which are captured inside of cells. This objective is realized by using the bidentate bases 4-(acetoxymethoxycarbonyl)phenyl-bis(3,5-dimethylpyrazolyl)methane (1) and 4-(acetoxymethoxy)phenyl-bis (3,5-dimethylpyrazolyl)methane (4) at facial (OC)3MnBr fragments yielding CORM-AM1 (2) and CORM-AM2 (5), respectively. Besides synthesis, crystal structures and spectroscopic properties we present targeted administration and intracellular accumulation of these AM-containing CORMs.

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