Oligonucleotide therapeutics, such as antisense oligonucleotides (ASOs) or short interfering RNA (siRNA), can modulate gene expression. It is possible to restore or delete gene function, as well as up- or down-regulate protein expression.

In drug discovery, stable isotope-labeled compounds are used for multiple purposes, specifically in mass spectrometric techniques. Molecules with a different molecular weight that maintain identical chemical, biological, and physical properties allows for precise quantification and imaging in various assays.

Anders Dahlén, AstraZeneca, Mölndal, Sweden, and colleagues have developed a convenient, fast, and general method for ³⁴S stable-isotope-labeling of oligonucleotides with a phosphorothioate backbone (pictured). The method is optimized for automated oligonucleotide synthesis. The team first developed a highly efficient, two‐step, one‐pot synthesis of ³⁴S‐labeled phenylacetyl disulfide (³⁴S‐PADS). The synthesis starts from ³⁴S‐enriched elemental sulfur, followed by a reduction with Super‐Hydride and a treatment of the resulting Li₂S₂ species with phenylacetyl chloride. ³⁴S‐PADS was then used for the labeling of oligonucleotides.

The ³⁴S‐labeled oligonucleotides were shown to have the same melting temperature, activity, and secondary structure as those of the corresponding unlabeled ³²S-oligonucleotide. ³⁴S-labeled oligonucleotides could be useful as internal standards for quantification in biological matrices, for the exploration of biotransformations, for metabolite studies, for biodistribution studies, etc.

• A Versatile and Convenient Synthesis of ³⁴S-Labeled Phosphorothioate Oligonucleotides,
  Rouven Stulz, Johan Meuller, Dženita Baždarević, Charlotte Wennberg Huldt, Roger Strömberg, Shalini Andersson, Anders Dahlén,
  ChemBioChem 2018.
  https://doi.org/10.1002/cbic.201800417