- A new method for synthesizing deoxynucleic guanidine (DNG) oligonucleotides that uses iodine as a mild and inexpensive coupling reagent is reported. This method eliminates the need for the toxic mercury salts and pungent thiophenol historically used in methods aimed at preparing DNG oligonucleotides. This coupling strategy was readily translated to a standard MerMade 12 oligonucleotide synthesizer with coupling yields of 95% and has enabled the synthesis of a 20-mer DNG oligonucleotide, the longest DNG strand to date, in addition to mixed DNA-DNG sequences with 3-9 DNG inserts. Importantly, DNG oligonucleotides exhibit robust unaided cellular uptake as compared to unmodified oligonucleotides without apparent cellular toxicity. Taken together, these findings should greatly increase the accessibility of cationic backbone modifications and assist in the development of oligonucleotide-based drugs.