The Johnstone Laboratory
Medicinal and Fundamental Inorganic Chemistry Research Group
RESEARCH
Our group works in two broadly distinct, yet related, areas: medicinal inorganic chemistry and fundamental main-group structure and bonding. Our medicinal inorganic chemistry efforts center on exploiting the unique properties of inorganic compounds to address problems related to human health. Research topics include: development of a small-molecule antidote for carbon monoxide poisoning, exploration of boron cluster compounds as X-ray contrast agents, and investigation of the antiparasitic and anticancer activity of Group 15 compounds. Related to this last point, we also explore the fundamental inorganic chemistry of heavy Group 15 elements in unprecedented bonding motifs. Finally, we collaborate with a number of other research groups to provide structural or physical inorganic insight into diverse chemical systems including peptidic materials, marine natural products, and cyclic polypeptides.
Carbon Monoxide Poisoning
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CO is a ligand widely employed in organometallic chemistry; its capacity for back-bonding stabilizes its interaction with electron-rich metal centers. CO is better known in the public sphere as the colorless, odorless, and poisonous gas that is emitted from automobile tailpipes and malfunctioning furnaces. Indeed, over 50,000 Americans visit emergency rooms for CO poisoning each year. The toxicity of CO in these contexts arises, in large part, from its avidity for binding metals. In particular, it binds to hemoglobin with a stability constant orders of magnitude greater than that of O2. Currently, the best option to treat an individual with CO poisoning is to place them in fresh air but, in the time it takes for CO to be fully cleared from the body, oxygen deprivation can result in serious injury and brain damage. We are capitalizing on our fundamental understanding of the coordination chemistry of CO to design molecules that can be used as antidotes to treat CO poisoning.
Pentavalent Antimonial Antileishmanials
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Leishmaniasis is a neglected tropical disease that affects over 6 million people in close to 100 different countries. The disease is caused by infection with parasites from the Leishmania genus that are transmitted by insect vectors. A mainstay treatment for the disease comprises a class of drugs known as the “pentavalent antimonials.” These drugs are formulated by combining a source of Sb(V) with carrier ligands, but despite having been used clinically for over a century, the structures of the molecules being administered remains unknown. We are seeking to use a variety of physical inorganic methods to uncover the structures of these compounds and use that molecular-level understanding to improve antileishmanial therapy.
Arsenic-Based Anticancer Agents
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Despite the common association of arsenic with toxicity, arsenic trioxide (As2O3) is approved by the FDA for the treatment of acute promyelocytic leukemia (APL). In addition to acting as a cytotoxic agent, arsenic trioxide appears to specifically target APL by inducing differentiation of the cancerous promyelocytes. As with many cytotoxic anticancer drugs, however, off-target toxicity results in a range of side effects including nausea, vomiting, fatigue, fever, headaches, tachycardia, swelling, and peripheral neuropathy. We are exploring whether organoarsenicals can provide a means of retaining the chemistry needed to exert an antileukemic effect, while affording the physicochemical control needed to mitigate side effects.
Novel Group 15 Bonding
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In the course of investigating the medicinal inorganic chemistry of Group 15 compounds, we came to appreciate that a number of important questions related to their fundamental structure and bonding remain unanswered. We use a variety of synthetic, computational, and physical inorganic methods to answer such questions. One area of particular interest centers on unprecedented unsaturated bonds involving heavy pnictogens.
