Aggregation of DNA oligomers with a neutral polymer facilitates DNA solubilization in organic solvents for DNA-encoded chemistry.

Chemical diversification of DNA-conjugated substrates is key in DNA-encoded library (DEL) synthesis and other nucleic acid-based technologies. One major challenge to the translation of synthesis methods to DNA-tagged substrates is the lack of solubility of the highly charged DNA oligomer in most organic solvents. A neutral acrylate block copolymer, devoid of any canonical nucleic acid-binding structure, tightly interacted with DNA oligonucleotides in their ammonium form, and solubilized them in nonpolar solvents such as dichloromethane, chloroform and toluene. The ternary DNA-copolymer-ammonium salt interactions led to the formation of aggregates in organic solvents whose size correlated with DNA oligomer length. This method for DNA solubilization was successfully applied to diversify DNA-tagged starting materials by three isocyanide multicomponent reactions (IMCR) with broad scope and excellent yields. The copolymer does not require tailored DNA conjugates and solubilized DNA oligomers of up to 80 nucleotides length. It will likely broaden the toolbox of DEL-compatible synthesis methods well beyond IMCR chemistry and it has application potential in other nucleic acid-based technologies that require a broadened solvent scope for nucleic acid conjugate synthesis.