Carbon Monoxide Releasing Molecules (CORMs), such as [fac-Mn(CO)3(Br)(bpCO2)]2- and CORM-401 ([Mn(CO)4(S2CNMe(CH2CO2H))]), have potential to release therapeutic levels of carbon monoxide. CO is a versatile signaling molecule that is produced endogenously and is suggested to exert anti-inflammatory, apoptotic, and anti-proliferative effects in several disease states.1 There are implications for physiological CO delivery by using endogenous hydrogen peroxide to trigger CO release of these manganese carbonyls since hypoxic tumors having significantly higher H2O2 concentrations compared to normal tissues.2,3 There is little quantitative information regarding the kinetics and reaction mechanisms of H2O2 with CORMs. To evaluate the viability of these pathways in cancer therapy, we have undertaken a quantitative kinetics study of the H2O2 oxidation of the water-soluble complexes [fac-Mn(CO)3(Br)(bpCO2)]2- and CORM-401 to characterize the mechanisms of these reactions. Previous studies in our group on the complex [fac-Mn(CO)3(Br)(bpCO2)]2- demonstrate that ~2.5 equivalents of CO were released upon H2O2 of the complex, and the first step of the reaction was likely a ligand substitution reaction.4 We also demonstrate the decay of the MLCT band at 408 nm of [fac-Mn(CO)3(Br)(bpCO2)]2- after the addition of H2O2, confirming that CO release resulted from the reaction. CORM-401 continuously releases CO under physiological conditions but has stable stock solutions over a period of 7 days. CORM-401 displays CO-dependent inhibition of cellular respiration, implying that it is possibly suitable for addressing susceptible heme proteins.5 We discuss the potential of carbon monoxide delivery to physiological targets and provide our future directions, which include similar kinetics studies on CORM-401.

Redox mediated carbon monoxide release from transition metal carbonyls—implications for physiological CO delivery by CORMs

ACS Spring 2022

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