Metal-Free CO Prodrugs Activated by Molecular Oxygen Protect against Doxorubicin-Induced Cardiomyopathy in Mice

Carbon monoxide has been extensively studied for its
various therapeutic
activities in cell cultures and animal models. Great efforts have
been made to develop noninhalational approaches for easy and controlled
CO delivery. Herein, we introduce a novel metal-free CO prodrug approach
that releases CO under near-physiological conditions. CO from the
quinone-derived CO prodrugs is initiated by general acid/base-catalyzed
tautomerization followed by oxidation by molecular oxygen to form
the key norbornadienone intermediate, leading to cheletropic CO release
only in an aerobic environment. Representative CO prodrug analog QCO-105 showed marked anti-inflammatory effects and HO-1 induction
activity in RAW264.7 macrophages. In a mouse model of doxorubicin-induced
cardiomyopathy, we show for the first time that the CO prodrug QCO-105 prevented cardiomyocyte injury, consistent with the
known organ-protective effects of HO-1 and CO. Overall, such a new
CO prodrug design serves as the starting point for developing CO-based
therapy in attenuating the cardiotoxicity of doxorubicin.