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

## TL;DR

A neutral polymer helps dissolve DNA in organic solvents, enabling chemical reactions with DNA-tagged molecules.

## Contribution

A new method for solubilizing DNA in nonpolar solvents using a neutral block copolymer.

## Key findings

- The polymer solubilized DNA oligomers in solvents like dichloromethane and chloroform.
- DNA solubilization enabled isocyanide multicomponent reactions with high yields.
- The method works for DNA oligomers up to 80 nucleotides long without tailored conjugates.

## Abstract

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.

A neutral block copolymer interacted with DNA oligomers and solubilized them in nonpolar solvents. This approach allowed for reacting DNA-tagged substrates by isocyanide multicomponent reactions with broad scope and excellent yields.