Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds

Yong Yao Loh, Kazunori Nagao, Andrew J. Hoover, David Hesk, Nelo R. Rivera, Steven L. Colletti, Ian W. Davies, David W.C. MacMillan

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146 Scopus citations

Abstract

Deuterium- and tritium-labeled pharmaceutical compounds are pivotal diagnostic tools in drug discovery research, providing vital information about the biological fate of drugs and drug metabolites. Herein we demonstrate that a photoredox-mediated hydrogen atom transfer protocol can efficiently and selectively install deuterium (D) and tritium (T) at a-amino sp3 carbon-hydrogen bonds in a single step, using isotopically labeled water (D2O or T2O) as the source of hydrogen isotope. In this context, we also report a convenient synthesis of T2O from T2, providing access to high-specific-activity T2O. This protocol has been successfully applied to the high incorporation of deuterium and tritium in 18 drug molecules, which meet the requirements for use in ligand-binding assays and absorption, distribution, metabolism, and excretion studies.

Original languageEnglish (US)
Pages (from-to)1182-1187
Number of pages6
JournalScience
Volume358
Issue number6367
DOIs
StatePublished - Dec 1 2017

All Science Journal Classification (ASJC) codes

  • General

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    Loh, Y. Y., Nagao, K., Hoover, A. J., Hesk, D., Rivera, N. R., Colletti, S. L., Davies, I. W., & MacMillan, D. W. C. (2017). Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science, 358(6367), 1182-1187. https://doi.org/10.1126/science.aap9674