Carbon Monoxide (CO) poisoning results in over 50,000 emergency department visits every year in the US and is one of the most common forms of poisoning worldwide. Oxygen is still the accepted treatment for CO poisoning but, depending on the amount of CO inhaled and the time it takes to receive treatment, O2 treatment may not be enough to prevent death or long-term damage. Despite the great need, there is no established antidote for CO poisoning. The toxicity of CO is derived from its interaction with diverse biological targets, and development of a treatment capable of addressing the myriad of symptoms that arise would be difficult. Instead, if the concentration of CO in the body can be lowered fast enough, the negative short-term and long-term effects of CO poisoning can be avoided. We are investigating novel meso-substituted porphyrin scaffolds to discover an antidote for CO poisoning. The Lindsay method was used to generate an aryl meso-substituted porphyrin core. Arylaldehydes featuring a 2,6-substitution pattern permit modulation of the bulk of the CO binding pocket either early in the synthesis or at a later stage via Pd-catalyzed coupling. Installation of four sulfonate groups imparted water solubility at physiological pH and also inhibit membrane permeability. The CO binding ability and half-life of our complexes were investigated using UV-vis spectroscopy, IR spectroscopy, and X-ray crystallography. A preliminary demonstration of efficacy was performed using purified human red blood cells (RBCs). A suspension of the cells was treated with sodium dithionite and then sparged with CO, generating carboxyhemoglobin (COHb). The COHb-containing RBCs were then washed with PBS and centrifuged to remove any excess dissolved CO. The COHb-containing RBCs were dosed with one of our iron(II) porphyrin compounds. UV-vis spectroscopy of the suspension confirmed the presence of the CO-bound form of our iron(II) porphyrin and the loss of CO from hemoglobin.

Progress towards an iron-porphyrin-based antidote for carbon monoxide poisoning

ACS Spring 2022

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