Belleau, B., Burba, J., Pindell, M. & Reiffenstein, J. Effect of deuterium substitution in sympathomimetic amines on adrenergic responses. Science 133, 102–104 (1961).
Gaffney, T. E., Hammar, C. G., Holmstedt, B. & McMahon, R. E. Ion specific detection of internal standards labeled with stable isotopes. Anal. Chem. 43, 307–310 (1971).
Simmons, E. M. & Hartwig, J. F. On the interpretation of deuterium kinetic isotope effects in C–H bond functionalizations by transition-metal complexes. Angew. Chem. Int. Ed. 51, 3066–3072 (2012).
Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. Deuterium- and tritium-labelled compounds: applications in the life sciences. Angew. Chem. Int. Ed. 57, 1758–1784 (2018).
Zachleder, V. et al. Stable isotope compounds-production, detection, and application. Biotechnol. Adv. 36, 784–797 (2018).
Derdau, V., Atzrod, J., Zimmermann, J., Kroll, C. & Bruckner, F. Hydrogen-deuterium exchange reactions of aromatic compounds and heterocycles by NaBD4-activated rhodium, platinum and palladium catalysts. Chem. Eur. J. 15, 10397–10404 (2009).
Elmore, C. S. In Annual Reports in Medicinal Chemistry Vol. 44 (ed. Macor, J. E.) 515–534 (Academic Press, 2009).
Allen, P. H. M., Hickey, J., Kingston, L. P. & Wilkinson, D. J. Metal-catalysed isotopic exchange labelling: 30 years of experience in pharmaceutical R&D. J. Label Compd. Radiopharm 53, 731–738 (2010).
Gant, T. G. Using deuterium in drug discovery: leaving the label in the drug. J. Med. Chem. 57, 3595–3611 (2014).
Mullard, A. Deuterated drugs draw heavier backing. Nat. Rev. Drug Discov. 15, 219–221 (2016).
Pirali, T., Serafini, M., Cargnin, S. & Genazzani, A. A. Applications of deuterium in medicinal chemistry. J. Med. Chem. 62, 5276–5297 (2019).
Mullard, A. FDA approves first drug for primary progressive multiple sclerosis. Nat. Rev. Drug Discov. 16, 305–305 (2017).
McGrath, N., Brichacek, A. M. & Njardarson, J. T. A graphical journey of innovative organic architectures that have improved our Lives. J. Chem. Educ. 87, 1348–1349 (2010).
Butler, M. A., Iwasaki, M., Guengerich, F. P. & Kadlubar, F. F. Human cytochrome P-450PA (P-450IA2), the phenacetin O-deethylase, is primarily responsible for the hepatic 3- demethylation of caffeine and N-oxidation of carcinogenic arylamines. Proc. Natl Acad. Sci. USA 86, 7696–7700 (1989).
Bernhardt, R. Cytochrome P450: structure, function, and generation of reactive oxygen Species. Rev. Physiol. Biochem. Pharm. 127, 138 (1995).
Furge, L. L. & Guengerich, F. P. Cytochrome P450 enzymes in drug metabolism and chemical toxicology. Biochem. Mol. Biol. Edu. 34, 66–74 (2006).
Yengi, L. G., Leung, L. & Kao, J. The evolving role of drug metabolism in drug discovery and development. Pharm. Res. 24, 842–858 (2007).
Meyer, A. H. et al. Cytochrome P450-catalyzed dealkylation of atrazine by Rhodococcus sp. strain NI86/21 involves hydrogen atom transfer rather than single electron transfer. Dalton Trans. 43, 12175–12186 (2014).
Dang, N. L., Hughes, T. B., Miller, G. P. & Swamidass, S. J. Computationally assessing the bioactivation of drugs by N-dealkylation. Chem. Res. Toxicol. 31, 68–80 (2018).
Elison, C., Rapoport, H., Laursen, R. & Elliott, H. W. Effect of deuteration of N-CH3 group on potency and enzymatic N-demethylation of morphine. Science 134, 1078–1079 (1961).
Miller, G. A. & Mucller, S. C. The metabolism of methylated aminoazo dyes. J. Biol. Chem. 258, 14445–14449 (1983).
Banach, T. E. & Dinnocenzo, J. P. Deprotonation of tertiary amine cation radicals. A direct experimental approach. J. Am. Chem. Soc. 111, 8646–8653 (1989).
Baciocchi, E. et al. Oxidative N-demethylation of N,N-dimethylanilines catalysed by lignin peroxidase: a mechanistic insight by a kinetic deuterium isotope effect study. Chem. Commun. 36, 393–394 (2000).
Guengerich, F. P. Kinetic deuterium isotope effects in cytochrome P450 oxidation reactions. J. Label. Compd. Radiopharm. 56, 428–431 (2013).
Yuya, N., Masashi, H., & Wataru, M. Industrial process of mono- alkylating a piperidine nitrogen in piperidine derivatives with deuterated- alkyl. U.S. Patent WO2019049918A1 (2019).
Jin, B., Dong, Q., Hung, G., & Kaldor, S. W. Heteroaromatic compounds as TYK2 inhibitors and their preparation. U.S. Patent WO2020086616A1 (2020).
Manley, P. W., Blasco, F., Mestan, J. & Aichholz, R. The kinetic deuterium isotope effect as applied to metabolic deactivation of imatinib to the des-methyl metabolite, CGP74588. Bioorg. Medicinal Chem. 21, 3231–3239 (2013).
Ratnikov, M. O. & Doyle, M. P. Mechanistic investigation of oxidative mannich reaction with tert-butyl hydroperoxide. The role of transition metal salt. J. Am. Chem. Soc. 135, 1549–1557 (2013).
Shen, Z. et al. Trideuteromethylation enabled by a sulfoxonium metathesis reaction. Org. Lett. 21, 448–452 (2019).
Zhu, M. et al. Detosylative (deutero)alkylation of indoles and phenols with (deutero)alkoxides. Org. Lett. 21, 7073–7077 (2019).
Atzrodt, J., Derdau, V., Kerr, W. J. & Reid, M. C-H functionalisation for hydrogen isotope exchange. Angew. Chem. Int. Ed. 57, 3022–3047 (2018).
Takahashi, M., Oshima, K. & Matsubara, S. Ruthenium catalyzed deuterium labelling of a-Carbon in primary alcohol and primary/secondary amine in D2O. Chem. Lett. 34, 192–193 (2005).
Neubert, L. et al. Ruthenium-catalyzed selective α, β-deuteration of bioactive amines. J. Am. Chem. Soc. 134, 12239–12244 (2012).
Pieters, G. et al. Regioselective and stereospecific deuteration of bioactive aza compounds by the use of ruthenium nanoparticles. Angew. Chem. Int. Ed. 53, 230–234 (2014).
Hale, L. V. A. & Szymczak, N. K. Stereoretentive deuteration of α-chiral amines with D2O. J. Am. Chem. Soc. 138, 13489–13492 (2016).
Kerr, W. J., Mudd, R. J., Reid, M., Atzrodt, J. & Derdau, V. Iridium-catalyzed Csp3-H activation for mild and selective hydrogen isotope exchange. ACS Catal. 8, 10895–10900 (2018).
Chang, Y. et al. Catalytic deuterium incorporation within metabolically stable β-amino C–H bonds of drug molecules. J. Am. Chem. Soc. 141, 14570–14575 (2019).
Loh, Y. et al. Photoredox-catalyzed deuteration and tritiation of pharmaceutical compounds. Science 358, 1182–1187 (2017).
Liu, C. et al. Controllable deuteration of halogenated compounds by photocatalytic D2O splitting. Nat. Commun. 9, 80–88 (2018).
Sklyaruk, J., Borghs, J. C., El-Sepelgy, O. & Rueping, M. Catalytic C1 alkylation with methanol and isotope‐labeled methanol. Angew. Chem. Int. Ed. 58, 775–779 (2019).
Zhang, M., Yuan, X., Zhu, C. & Xie, J. Deoxygenative deuteration of carboxylic acids with D2O. Angew. Chem. Int. Ed. 58, 312–316 (2019).
Geng, H. et al. Practical synthesis of C1 deuterated aldehydes enabled by NHC catalysist. Nat. Cat. 2, 1071–1077 (2019).
Liu, W. et al. Mesoionic carbene (MIC)-catalyzed H/D exchange at formyl groups. Chem 5, 2484–2494 (2019).
Isin, E. M., Elmore, C. S., Nilsson, G. N., Thompson, R. A. & Weidolf, L. Use of radiolabeled compounds in drug metabolism and pharmacokinetic studies. Chem. Res. Toxicol. 25, 532–542 (2012).
Nelson, S. D. & Trager, W. F. The use of deuterium isotope effects to probe the active site properties, mechanism of cytochrome P450-catalyzed reactions, and mechanisms of metabolically dependent toxicity. Drug Metab. Dispos. 31, 1481–1498 (2003).
Dogutan, D. K. & Nocera, D. G. Artificial photosynthesis at efficiencies greatly exceeding that of natural photosynthesis. Acc. Chem. Res. 52, 3143–3148 (2019).
Kisch, H. Semiconductor photocatalysis—mechanistic and synthetic aspects. Angew. Chem. Int. Ed. 52, 812–847 (2013).
Kisch, H. Semiconductor photocatalysis for chemoselective radical coupling reactions. Acc. Chem. Res. 50, 1002–1010 (2017).
Ghosh, I. et al. Organic semiconductor photocatalyst can bifunctionalize arenes and heteroarenes. Science 365, 360–366 (2019).
Wang, X. et al. A metal-free polymeric photocatalyst for hydrogen production from water under visible light. Nat. Mater. 8, 76–80 (2009).
Kessler, F. K. et al. Functional carbon nitride materials-design strategies for electrochemical devices. Nat. Rev. Mater. 2, 17030 (2017).
Qiu, C. et al. Highly crystalline K-intercalated polymeric carbon nitride for visible-light photocatalytic alkenes and alkynes deuterations. Adv. Sci. 6, 1801403–1801409 (2019).
Schönherr, H. & Cernak, T. Profound methyl effects in drug discovery and a call for new C-H methylation reactions. Angew. Chem. Int. Ed. 52, 12256–12267 (2013).
Chatterjee, J., Gilon, C., Hoffman, A. & Kessler, H. N-methylation of peptides: a new perspective in medicinal chemistry. Acc. Chem. Res. 41, 1331–1342 (2008).
Barreiro, E. J., Kümmerle, A. E. & Fraga, C. A. M. The methylation effect in medicinal chemistry. Chem. Rev. 111, 5215–5246 (2011).
White, T. R. et al. On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat. Chem. Biol. 7, 810–817 (2011).
Chatterjee, J., Rechenmacher, F. & Kessler, H. N-methylation of peptides and proteins: an important element for modulating biological functions. Angew. Chem. Int. Ed. 52, 254–269 (2013).
Natte, K., Neumann, H., Beller, M. & Jagadeesh, R. V. Transition-metal-catalyzed utilization of methanol as a C1 source in organic synthesis. Angew. Chem. Int. Ed. 56, 6384–6394 (2017).
Cernak, T., Dykstra, K. D., Tyagarajan, S., Vachal, P. & Krska, S. W. The medicinal chemist’s toolbox for late stage functionalization of drug-like molecules. Chem. Soc. Rev. 45, 546–576 (2016).
Kitamura, K. et al. Synthesis of [N-13CH3] drugs (chlorpromazine, triflupromazine and promazine). J. Label Compd. Radiopharm. 43, 865–872 (2000).
Elmore, C. S. & Bragg, R. A. Isotope chemistry; a useful tool in the drug discovery arsenal. Bioorg. Med. Chem. Lett. 25, 167–171 (2015).
Syroeshkin, A. et al. D/H control of chemical kinetics in water solutions under low deuterium concentrations. Chem. Eng. J. 377, 119827 (2019).
Kitamura, K. et al. Dissociation constants of phenothiazine drugs incorporated in phosphatidylcholine bilayer of small unilamellar vesicles as determined by carbon-13 nuclear magnetic resonance spectrometric titration. BBA-Biomembranes 61-67, 2004 (1661).
Li, Y., Sorribes, I., Yan, T., Junge, K. & Beller, M. Selective methylation of amines with carbon dioxide and H2. Angew. Chem. Int. Ed. 52, 12156–12160 (2013).