Water-dispersible ruthenium nanocatalyst enables efficient deuterium and tritium labeling of complex molecules in aqueous media.

The development of biologics as therapeutic agents necessitates efficient catalytic methods for direct incorporation of hydrogen isotopes (deuterium, tritium) from readily available sources in aqueous media. Isotopic labeling is critical for understanding drug metabolism and pharmacokinetics, leveraging the deuterium kinetic isotope effect (KIE) to improve drug stability. Current methods often struggle with the direct, regioselective labeling of complex, polar molecules and biologics in water, creating a significant gap in drug discovery and development.

Researchers synthesized and characterized water-dispersible ruthenium nanoparticles stabilized by the commercially available phosphine ligand sSPhos. These nanocatalysts were then applied to carbonyl reduction reactions under low-pressure deuterium (D2) and tritium (T2) atmospheres in aqueous media. A diverse range of aldehyde precursors, including the large cyclic peptide derivative acetyl-cyclosporin A, were tested. Mechanistic investigations were performed to understand the deuterium incorporation pathways. The synthetic utility was further demonstrated by applying a two-step sequence (Bobbitt's salt-mediated oxidation followed by reductive deuteration) to the active pharmaceutical ingredient losartan and a peptide-derived cathepsin-cleavable linker.

The novel ruthenium nanocatalyst successfully enabled the synthesis of a broad range of functionalized deuterated alcohols. These products were obtained in high isotopic enrichment from diverse aldehyde precursors, demonstrating the catalyst's versatility. Notably, the method proved effective for labeling complex molecules, including the large cyclic peptide derivative acetyl-cyclosporin A. Mechanistic studies revealed that deuterium incorporation, in some cases, proceeded through both hydrogen isotope exchange on the aldehyde starting material and the reductive deuteration pathway. The synthetic utility for regioselective labeling was further highlighted by the successful application of a two-step oxidation-reduction sequence to losartan and a peptide-derived linker.

The methodology also achieved a successful tritiation experiment, underscoring its broad potential for challenging hydrogen isotope labeling of complex polar molecules and biologics.