AbstractCO-binding Bis-Pocket Iron Porphyrins: Towards the Development of a CO Poisoning Antidote By Daniel G. Droege A dissertation submitted in partial satisfaction of the requirements for the degree of Doctor of Philosophy in Chemistry

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. Presented here is the initial phase of the investigation of a novel meso-substituted porphyrin scaffold to discover an antidote for CO poisoning. The Lindsey 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 Caryl-Caryl coupling. Optimization of the coupling reaction was undertaken to facilitate derivatization. Installation of four sulfonate groups imparted water solubility at physiological pH and also inhibited membrane permeability. The modular nature of this scaffold allowed for the derivatization of multiple complexes. The solubility, CO binding ability, and oxidative stability of the complexes were investigated using UV-vis spectroscopy, IR spectroscopy, and X-ray crystallography. A preliminary demonstration of efficacy was performed using purified 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 the iron(II) porphyrin and the loss of CO from hemoglobin. Using the knowledge gained from the first set of derivatives of this scaffold, new complexes will be targeted. This work will prove useful in the rapid advancement of novel porphyrin derivatives to uncover a small molecule CO poisoning antidote.

Antimony(Sb)-containing molecules have a rich therapeutic history. Their most significant clinical use in modern medicine is in the treatment of the neglected tropical disease leishmaniasis. Up to a million new cases of leishmaniasis are reported annually, and the disease disproportionately affects populations of low- and middle-income countries. The current frontline treatments for leishmaniasis are the pentavalent antimonials: meglumine antimoniate (Glucantime) and sodium stibogluconate (Pentostam). Although effective, the pentavalent antimonials have severe side-effects and resistance to the drugs is mounting. Despite the pentavalent antimonials having been used for nearly a century, their structures and mechanism of action are still unknown. Elucidation of these drugs’ structures would allow for derivatization that could reduce toxicity while increasing the efficacy of treatment. Furthermore, structural knowledge of the pentavalent antimonials could prove pivotal in the elucidation of their mechanism of action. Presented here are our initial attempts to develop and apply techniques that will allow for better understanding of antimony and its interactions with the ligands employed in the synthesis of the pentavalent antimonials. Quantum theory of atoms in molecules (QTAIM) was used to elucidate the character of bonding interactions between pnictogens and oxygen. Pentaphenylantimony served as a proof-of-concept compound for an exploration into the use of physical inorganic techniques such as X-ray absorption spectroscopy to provide insight to the geometry of Sb-containing compounds. The solution-and solid-state structures of a series of Sb-diolate compounds were investigated via 1H and 13C{1H} nuclear magnetic resonance (NMR) spectroscopy and X-ray crystallography to gain a better understanding of how an Sb center is coordinated by secondary and primary alkoxides with varying stereochemistry. Trends in the chemical shifts from NMR spectra of these compounds were observed as a product of the stereochemistry of the diol chelating the Sb center. Elucidation of these spectroscopic signatures allows for future insight into Sb-containing molecules and their structures. The work described in this dissertation provides a foundational framework for understanding the interactions between polyalcohols and Sb, an important step toward improved Sb-containing therapeutics.