Michigan Cancer Research Fund                                                                                            American Cancer Society
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Research Project Description from Daryl Staveness, PhD, 2016 MCRF Fellow

Project Name: Re-Engineering Toxic Aniline-Based Drugs with 1-Aminonorbornane Isosteres

Taking an aspirin technically qualifies as chemotherapy, but typically “chemo” tends to elicit a much more negative imagery. While there are multiple reasons a drug might have associated side effects, one rather common issue in drug development is adverse metabolism. The liver is designed to clear many foreign substances from the body, but in some cases, the liver will process active pharmaceutical ingredients into highly reactive metabolites, ultimately resulting in toxicity. This problem has stopped many promising leads from reaching approval and has even led to drugs being removed from the market.

Importantly, this reactivity (i.e. processing by liver enzymes) is necessarily tied to the chemical structure of the drug, and through decades of medicinal chemistry research, we can generally identify substructures that are at a high risk for deleterious metabolism (these are termed “structural alerts”). Anilines are one such substructure and have even been described as “the most notorious” of them all. Unfortunately, while some structural alerts can be mimicked with other motifs such that the desired pharmacology is achieved with a reduced risk of deleterious metabolism, nothing in our current chemical toolbox reliably serves as a metabolically-inert substitute for anilines. This project seeks to change that paradigm through the preparation and evaluation of 1-aminonorbornanes (aminoNBs).