Lijun Xue; Weijie Liu; Shu Li; Nicolas Duchemin; Mengjia Lou; Jingyu Yuan; Huanqing Zhang; Junyun Chen; Weina Yu; Kexin Yang; Yunjin Hu
Bioconjugate Chem., 2023, 34(8), 1366-1373
https://doi.org/10.1021/acs.bioconjchem.3c00138

Abstract

We herein present the first application of the on-DNA Morita-Baylis-Hillman (MBH) reaction for the creation of pharmaceutically relevant targeted covalent inhibitors (TCIs) with an α-hydroxyl Michael acceptor motif. Adapting a DNA-compatible organocatalytic process, this MBH reaction for covalent selection-capable DNA encoded library (DEL) synthesis grants access to densely functionalized and versatile precursors to explore novel chemical space for molecule recognition in drug discovery. Most importantly, this methodology sheds light on potentially unexpected reaction outcomes of the MBH reaction.