Metal-Free\nCO Prodrugs Activated by Molecular Oxygen\nProtect against Doxorubicin-Induced Cardiomyopathy in Mice

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