C-N Coupling of DNA-Conjugated (Hetero)aryl Bromides and Chlorides for DNA-Encoded Chemical Library Synthesis.

Autor:	Chen YC; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Faver JC; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Ku AF; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Miklossy G; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Riehle K; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Bohren KM; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Ucisik MN; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Matzuk MM; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Yu Z; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States., Simmons N; Center for Drug Discovery, Department of Pathology and Immunology, Baylor College of Medicine, Houston, Texas 77030, United States.
Jazyk:	angličtina
Zdroj:	Bioconjugate chemistry [Bioconjug Chem] 2020 Mar 18; Vol. 31 (3), pp. 770-780. Date of Electronic Publication: 2020 Feb 21.
DOI:	10.1021/acs.bioconjchem.9b00863
Abstrakt:	DNA-encoded chemical library (DECL) screens are a rapid and economical tool to identify chemical starting points for drug discovery. As a robust transformation for drug discovery, palladium-catalyzed C-N coupling is a valuable synthetic method for the construction of DECL chemical matter; however, currently disclosed methods have only been demonstrated on DNA-attached (hetero)aromatic iodide and bromide electrophiles. We developed conditions utilizing an N -heterocyclic carbene-palladium catalyst that extends this reaction to the coupling of DNA-conjugated (hetero)aromatic chlorides with (hetero)aromatic and select aliphatic amine nucleophiles. In addition, we evaluated steric and electronic effects within this catalyst series, carried out a large substrate scope study on two representative (hetero)aryl bromides, and applied this newly developed method within the construction of a 63 million-membered DECL.
Databáze:	MEDLINE
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