title: Systematic evaluation and optimization of modification reactions of oligonucleotides with amines and carboxylic acids for the synthesis of DNA-encoded chemical libraries.
abstract: DNA-encoded chemical libraries are collections of small molecules, attached to DNA fragments serving as identification barcodes, which can be screened against multiple protein targets, thus facilitating the drug discovery process. The preparation of large DNA-encoded chemical libraries crucially depends on the availability of robust synthetic methods, which enable the efficient conjugation to oligonucleotides of structurally diverse building blocks, sharing a common reactive group. Reactions of DNA derivatives with amines and/or carboxylic acids are particularly attractive for the synthesis of encoded libraries, in view of the very large number of building blocks that are commercially available. However, systematic studies on these reactions in the presence of DNA have not been reported so far. We first investigated conditions for the coupling of primary amines to oligonucleotides, using either a nucleophilic attack on chloroacetamide derivatives or a reductive amination on aldehyde-modified DNA. While both methods could be used for the production of secondary amines, the reductive amination approach was generally associated with higher yields and better purity. In a second endeavor, we optimized conditions for the coupling of a diverse set of 501 carboxylic acids to DNA derivatives, carrying primary and secondary amine functions. The coupling efficiency was generally higher for primary amines, compared to secondary amine substituents, but varied considerably depending on the structure of the acids and on the synthetic methods used. Optimal reaction conditions could be found for certain sets of compounds (with conversions >80%), but multiple reaction schemes are needed when assembling large libraries with highly diverse building blocks. The reactions and experimental conditions presented in this article should facilitate the synthesis of future DNA-encoded chemical libraries, while outlining the synthetic challenges that remain to be overcome.
authors: Institute of Pharmaceutical Sciences , ETH Zürich, Vladimir-Prelog Weg 1-5/10, 8093 Zürich, Switzerland.
authors: Raphael M
authors: RM
authors: Franzini
authors: Florent
authors: F
authors: Samain
authors: Maaly
authors: M
authors: Abd Elrahman
authors: Gediminas
authors: G
authors: Mikutis
authors: Angela
authors: A
authors: Nauer
authors: Mauro
authors: M
authors: Zimmermann
authors: Jörg
authors: J
authors: Scheuermann
authors: Jonathan
authors: J
authors: Hall
authors: Dario
authors: D
authors: Neri
mesh_terms: D000447:Aldehydes / Q000737:chemistry; D000586:Amination; D000588:Amines / Q000737:chemistry*; D002264:Carboxylic Acids / Q000737:chemistry*; D060326:Chemistry Techniques, Synthetic; D004247:DNA / Q000737:chemistry*; D007475:Ion Exchange Resins / Q000737:chemistry; D009841:Oligonucleotides / Q000737:chemistry*; D010084:Oxidation-Reduction; D054852:Small Molecule Libraries / Q000138:chemical synthesis* / Q000737:chemistry*
chemical_list: D000447:Aldehydes; D000588:Amines; D002264:Carboxylic Acids; D007475:Ion Exchange Resins; D009841:Oligonucleotides; D054852:Small Molecule Libraries; D004247:DNA