Optimized Reaction Conditions for Amide Bond Formation in DNA-Encoded Combinatorial Libraries.
DNA-encoded combinatorial libraries are increasingly being used as tools for the discovery of small organic binding molecules to proteins of biological or pharmaceutical interest. In the majority of cases, synthetic procedures for the formation of DNA-encoded combinatorial libraries incorporate at least one step of amide bond formation between amino-modified DNA and a carboxylic acid. We investigated reaction conditions and established a methodology by using 1-ethyl-3-(3-(dimethylamino)propyl)carbodiimide, 1-hydroxy-7-azabenzotriazole and N,N'-diisopropylethylamine (EDC/HOAt/DIPEA) in combination, which provided conversions greater than 75% for 423/543 (78%) of the carboxylic acids tested. These reaction conditions were efficient with a variety of primary and secondary amines, as well as with various types of amino-modified oligonucleotides. The reaction conditions, which also worked efficiently over a broad range of DNA concentrations and reaction scales, should facilitate the synthesis of novel DNA-encoded combinatorial libraries.
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.
Yizhou
Y
Li
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.
Elena
E
Gabriele
Philochem AG , Libernstrasse 3, 8112 Otelfingen, Switzerland.
Florent
F
Samain
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.
Nicholas
N
Favalli
Philochem AG , Libernstrasse 3, 8112 Otelfingen, Switzerland.
Filippo
F
Sladojevich
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.
Jörg
J
Scheuermann
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology (ETH Zürich) , Vladimir-Prelog-Weg 3, CH-8093 Zürich, Switzerland.
Dario
D
Neri
D000577:Amides / Q000737:chemistry*; D000588:Amines / Q000737:chemistry; D002264:Carboxylic Acids / Q000737:chemistry; D020650:Combinatorial Chemistry Techniques; D004247:DNA / Q000737:chemistry*; D055808:Drug Discovery; D009841:Oligonucleotides / Q000737:chemistry; D011506:Proteins / Q000737:chemistry; D054852:Small Molecule Libraries / Q000737:chemistry*
D000577:Amides; D000588:Amines; D002264:Carboxylic Acids; D009841:Oligonucleotides; D011506:Proteins; D054852:Small Molecule Libraries; D004247:DNA
DNA-encoded chemical libraries; amide bond formation; bioconjugation; synthesis