Using Inorganic Chemistry to Understand and Solve Health-Related Problems

Project Summary. This award is sought to support the foundation of a research program that will broadly capitalize on the unique properties of inorganic compounds to afford medicinal solutions that are complementary to those accessible via traditional organic medicinal chemistry. The underlying philosophy of the research program is that the historic and continued success of the medicinal chemistry enterprise derives from the diversity of structures and reactivities that can be accessed using organic chemistry. This diversity notwithstanding, there is a greater diversity of properties that can be accessed using inorganic compounds in addition to organic ones. There will be instances in which the chemistry of inorganic substances, or the methodologies and approaches of inorganic chemists, will allow problems to be solved that would otherwise remain intractable. During this award period, the problems that will be tackled are: (i) the lack of an antidote for carbon monoxide poisoning, and (ii) a gap in the understanding of the chemistry and biology of antimony-containing drugs that are widely used to treat the neglected tropical disease leishmaniasis. The need for an antidote for carbon monoxide poisoning stems from the fact that conventional oxygen administration cannot clear carbon monoxide from the body quickly enough in cases of severe poisoning. My research group has previously obtained proof-of-principle data indicating that a small-molecule iron-porphyrin platform can exhibit the chemistry needed by an antidote. I propose to explore this modular platform to uncover the relationships that govern carbon monoxide sequestration and biological efficacy. The parasitic disease leishmaniasis is widely treated with two antimony-containing drugs. Although effective, treatment with these drugs is accompanied by severe side effects. Efforts to improve upon these drugs are hampered by our lack of knowledge concerning their chemistry and biology. We have recently demonstrated that a range of physical inorganic techniques can be used to gain insight into the chemistry of antimony compounds, and we will apply these methods to the antileishmanial drugs. A particular focus will be placed on uncovering the molecular structures of the drugs and their biotransformation products and establishing spectroscopic signatures that will allow these transformations to be followed in complex biological media and environments. Although distinct, these two areas of investigation both center on problems that require a combined expertise in fundamental inorganic chemistry, medicinal bioinorganic chemistry, and biological chemistry. My past training, complemented by key collaborations, will allow me to establish an impactful research program in medicinal inorganic chemistry.