Automated synthesis of phosphorus-sulfur analogs of nucleic acids-25 years on: potential therapeutic agents and proven utility in biotechnology

Replacement of non-bridging oxygen by sulfur in one or more internucleotide linkages in synthetic oligodeoxynucleotides (ODNs) was first fully automated in 1984. The present account highlights how ready access to these nuclease-resistant, phosphorothioate-modified oligodeoxynucleotides (PS-ODNs) and chemically related compounds, notably phosphorothiolates, has enabled remarkably broad advances across basic science, medical research, and biotechnology. These developments exemplify how an initially narrow-scope chemical reaction-in this case, automated sulfurization of an internucleoside phosphite-can give rise to diverse applications far beyond initial expectations.