34 S: A New Opportunity for the Efficient Synthesis of Stable Isotope Labeled Compounds

Abstract

The synthesis of stable isotope labeled (SIL) complex drug molecules with a ≥3 mass unit increase from the parent compound is essential for drug discovery and development. Typical approaches that rely on ² H, ¹³ C, and ¹⁵ N isotopes can be very challenging or even intractable, and can delay the drug development process. This work introduces a new concept for the synthesis of labeled compounds that relies on the use of ³⁴ S. The synthetic utility of ³⁴ S was demonstrated with the efficient synthesis of [³⁴ S]phosphorothioates [³⁴ S₂ ]-PS-ODNs-TTT and [¹³ C, ¹⁵ N, ³⁴ S]-ceftolozane. In addition, a procedure for the direct oxidation of phosphites to [³⁴ S]phosphorothioates using elemental ³⁴ S without isotope dilution was developed.

Keywords: absolute bioavailability; isotopic labeling; oligonucleotides; solid-phase synthesis; sulfur-34.