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Reactivity and Discovery Enabled by Molecular Design

Bio: Simon Rössler obtained a B.Sc. and M.Sc. in chemistry from the ETH Zürich in Switzerland, during which time he conducted his master’s thesis under the supervision of Tobias Ritter at Harvard University. He then returned to ETH Zürich to join the group of Erick M. Carreira for his Ph.D. focused on transition metal catalysis, working on mechanistic studies, method development, and total synthesis. In 2020, he moved back to Boston to join the groups of Stephen L. Buchwald and Bradley L. Pentleute at MIT as a Swiss National Science Foundation postdoctoral fellow, where he is currently developing a novel drug discovery platform.

Abstract: The design of molecular scaffolds functions as a driver of reactivity and discovery. A pyridinium reagent was designed to undergo an unprecedented heterolytic fragmentation upon single electron reduction to furnish a synthetically viable N-pyridyl radical cation. This reactive species was leveraged for the C−H amination of (hetero)arenes to yield N-aryl pyridinium products, which enable access to diverse nitrogen scaffolds. The design of peptide–small molecule conjugates has afforded a novel discovery platform termed peptide-encoded libraries (PELs), wherein the peptide functions as an optimized carrier of information to encode the identity of the small molecule. The chemical stability of the peptide-based tag allows the implementation of palladium-mediated reactions to efficiently synthesize PELs with broad chemical diversity and high purity. The resulting PELs featuring up to 40k small molecules, each equipped with a unique encoding peptide, were leveraged in affinity selections for the de novo discovery of small molecule binders for tumor-involved proteins.

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