Andrei Yudin
University of Toronto
Talk Title
Development of Privileged Macrocyclic Motifs Using the Tools of Chemical Synthesis
Presentation Time
SESSION 7: FROM NATURAL PRODUCTS TO UNNATURAL BIOACTIVE PEPTIDES
Tuesday, June 27, 2023, at 10:00 am - 10:25 am
Favorable drug-like properties is a fundamental challenge in the development of bioactive macrocycles. To achieve this objective, chemists have resorted to various strategies, the most common of which is deployment of N-methylated amino acids and/or unnatural amino acids. We recently explored a different approach and investigated the effect of heterocyclic grafts on the passive membrane permeability of macrocycles.
Through stepwise substitution of amino acid residues for azole rings, we have shown that lipophilicity and PAMPA permeability of a macrocycle can be vastly improved. Overall, changes in permeability do not scale linearly as more heterocycles are incorporated, underscoring the subtleties of conformation-property relationships in this class of molecule. NMR analysis and molecular dynamics simulations provide insights into the structural consequences of the added heterocycles. This study paves a way to the discovery of privileged macrocyclic scaffolds for drug discovery.
References
1. Huh, S., Saunders, G. J., and Yudin, A. K. Single Atom Ring Contraction of Peptide Macrocycles Using Cornforth Rearrangement. Angew. Chem. Int. Ed. 2022, 62, 5, e202214729
2. Saunders, G. J. and Yudin, A. K.. Property-Driven Development of Passively Permeable Macrocyclic Scaffolds Using Heterocycles. Angew. Chem. Int. Ed. 2022, 134, 33, e202206866
3. “Navigating complex peptide . Navigating Complex Peptide Structures Using Macrocycle Conformational Maps. RSC Chem. Biol. 2022, 3, 739–747
4. Kobori, S., Huh, S., Appavoo, S., and Yudin, A. K.. Two-Dimensional Barriers for Probing Conformational Shifts in Macrocycles. J. Am. Chem. Soc. 2021, 143, 13, 5166–5171
Professor Andrei K. Yudin is a Tier I Canada Research Chair in Medicine by Design at the University of Toronto. He obtained his B.Sc. degree at the Moscow State University in 1992 and his Ph.D. degree at the University of Southern California under the direction of Professors G. K. Surya Prakash and George A. Olah in 1996. He subsequently took up a postdoctoral position in the laboratory of Professor K. Barry Sharpless at the Scripps Research Institute. In 1998, he started his independent career at the University of Toronto. He received early tenure, becoming an Associate Professor in 2002, and received an early promotion to the rank of a Full Professor in 2007. He currently serves as an Associate Editor for Chemical Science, handling submissions in the area of organic chemistry.
