Selective functionalization at N²-position of guanine in oligonucleotides via reductive amination

Chemo- and site-specific modifications in oligonucleotides have wide applicability as mechanistic probes in chemical biology. However, methods that label specific sites in nucleic acids are scarce, especially for labeling DNA/RNA from biological or enzymatic sources rather than synthetic ones. Here we have employed a classical reaction, reductive amination, to selectively functionalize the N²-amine of guanosine and 2'-deoxyguanosine monophosphate (GMP/dGMP). This method specifically modifies guanine in DNA and RNA oligonucleotides, while leaving the other nucleobases unaffected. Using this approach, we have successfully incorporated a reactive handle chemoselectively into nucleic acids for further functionalization and downstream applications.