Xianfeng Li; Juan Zhang; Changyang Liu; Jie Sun; Yangfeng Li; Gong Zhang; Yizhou Li
Chem. Sci., 2022, 13, 13100-13109
https://doi.org/10.1039/D2SC04482J

Abstract

Forging carbon-carbon (C-C) linkage in DNA-encoded combinatorial library synthesis represents a fundamental task for drug discovery, especially with broad substrate scope and exquisite functional group tolerance. Here we reported the palladium-catalyzed Suzuki-Miyaura , Heck and Hiyama type cross-coupling via DNA-conjugated aryl diazonium intermediates for DNA-encoded chemical library (DEL) synthesis. Starting from commodity arylamines, this synthetic route facilely delivers vast chemical diversity under mild temperature and pH, thus circumventing damage to fragile functional groups. Given its orthogonality with traditional aryl halide-based cross-coupling, the aryl diazonium-centered strategy expands the compatible synthesis of complex C-C bond-connected scaffolds. In addition, DNA-tethered pharmaceutical compounds (e.g., HDAC inhibitor) are constructed without decomposition of susceptible bioactive warheads (e.g., hydroxamic acid), emphasizing the superiority of the aryl diazonium-based approach. Together with the convenient transformation to aryl azide photo-crosslinker, aryl diazonium’s DNA-compatible diversification synergistically demonstrated its competence to create medicinally relevant combinatorial libraries and investigate protein-ligand interactions in pharmaceutical research.