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.