Anna Marstall

My research work focuses on developing strategies for synthesizing and characterizing 14-membered sulfur-containing macrocycles. These sulfonamide compounds are generally biologically active and are therefore pharmaceutically significant as potential drug candidates. The preorganization and three-dimensional flexibility of these macrocyclic compounds make them ideal candidates for profiling in the drug-discovery effort.

Initial synthesis of these molecules involves a three-component coupling between a modified amino acid derivative, an amine, and a chlorosulfonyl isocyanate (CSI) backbone. Ring-closing metathesis is used to form the cyclized product. Following the coupling, strategic placement of nitrogen molecules throughout the ring allows for selective installation of electrophiles, allowing for several analogues of the initial macrocycle to be created. The functionality of these large sulfur-containing molecules comes from their multiple electrophilic regions, including Michael acceptors, that aid in the selective installation of various functional groups.

Following synthesis of these macrocycles, we plan to carry out reactivity profiling to show that these molecules are reactive towards cysteine or other reactive amino acids. Cysteine-reactive macrocycles are not well-characterized in recent literature, which is why development and profiling of these macrocycles is crucial in determining their application in complex biological pathways. The ultimate goal of this project involves activity-based protein profiling studies to determine the potential use of these molecules as chemical probes.