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Development and application of bond cleavage reactions in bioorthogonal chemistry

Abstract

Bioorthogonal chemical reactions are a thriving area of chemical research in recent years as an unprecedented technique to dissect native biological processes through chemistry-enabled strategies. However, current concepts of bioorthogonal chemistry have largely centered on 'bond formation' reactions between two mutually reactive bioorthogonal handles. Recently, in a reverse strategy, a collection of 'bond cleavage' reactions has emerged with excellent biocompatibility. These reactions have expanded our bioorthogonal chemistry repertoire, enabling an array of exciting new biological applications that range from the chemically controlled spatial and temporal activation of intracellular proteins and small-molecule drugs to the direct manipulation of intact cells under physiological conditions. Here we highlight the development and applications of these bioorthogonal cleavage reactions. Furthermore, we lay out challenges and propose future directions along this appealing avenue of research.

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Figure 1: Representatives of bioorthogonal ligation reactions.
Figure 2: Emerging bioorthogonal cleavage reactions.
Figure 3: Bioorthogonal cleavage chemistry for protein activation.
Figure 4: Bioorthogonal cleavage chemistry for cell engineering.
Figure 5: Bioorthogonal cleavage chemistry on small molecules.
Figure 6: Outlook for bioorthogonal cleavage chemistry.

References

  1. Prescher, J.A. & Bertozzi, C.R. Chemistry in living systems. Nat. Chem. Biol. 1, 13–21 (2005). A landmark paper describing the fundamental concepts of bioorthogonal chemistry.

    CAS  PubMed  Google Scholar 

  2. Sletten, E.M. & Bertozzi, C.R. Bioorthogonal chemistry: fishing for selectivity in a sea of functionality. Angew. Chem. Int. Ed. Engl. 48, 6974–6998 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Bertozzi, C.R. A decade of bioorthogonal chemistry. Acc. Chem. Res. 44, 651–653 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Walsh, C.T., Garneau-Tsodikova, S. & Gatto, G.J. Protein posttranslational modifications: the chemistry of proteome diversifications. Angew. Chem. Int. Ed. Engl. 44, 7342–7372 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Baker, M. Direct protein control. Nat. Methods 9, 443–447 (2012).

    Article  CAS  Google Scholar 

  6. Rakhit, R., Navarro, R. & Wandless, T.J. Chemical biology strategies for posttranslational control of protein function. Chem. Biol. 21, 1238–1252 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Muñoz, J. & Heck, A.J.R. From the human genome to the human proteome. Angew. Chem. Int. Ed. Engl. 53, 10864–10866 (2014).

    Article  PubMed  CAS  Google Scholar 

  8. Laughlin, S.T., Baskin, J.M., Amacher, S.L. & Bertozzi, C.R. In vivo imaging of membrane-associated glycans in developing zebrafish. Science 320, 664–667 (2008). This work represents an appealing example on how bioorthogonal chemistry can outcompete conventional approaches in studying certain biological questions.

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Zhang, G., Zheng, S., Liu, H. & Chen, P.R. Illuminating biological processes through site-specific protein labeling. Chem. Soc. Rev. 44, 3405–3417 (2015).

    Article  CAS  PubMed  Google Scholar 

  10. Lang, K. & Chin, J.W. Bioorthogonal reactions for labeling proteins. ACS Chem. Biol. 9, 16–20 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Patterson, D.M., Nazarova, L.A. & Prescher, J.A. Finding the right (bioorthogonal) chemistry. ACS Chem. Biol. 9, 592–605 (2014).

    Article  CAS  PubMed  Google Scholar 

  12. McKay, C.S. & Finn, M.G. Click chemistry in complex mixtures: bioorthogonal bioconjugation. Chem. Biol. 21, 1075–1101 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ramil, C.P. & Lin, Q. Bioorthogonal chemistry: strategies and recent developments. Chem. Commun. (Camb.) 49, 11007–11022 (2013).

    Article  CAS  Google Scholar 

  14. Thirumurugan, P., Matosiuk, D. & Jozwiak, K. Click chemistry for drug development and diverse chemical-biology applications. Chem. Rev. 113, 4905–4979 (2013).

    Article  CAS  PubMed  Google Scholar 

  15. Borrmann, A. & van Hest, J.C.M. Bioorthogonal chemistry in living organisms. Chem. Sci. 5, 2123–2134 (2014).

    Article  CAS  Google Scholar 

  16. Yang, M., Li, J. & Chen, P.R. Transition metal-mediated bioorthogonal protein chemistry in living cells. Chem. Soc. Rev. 43, 6511–6526 (2014).

    Article  CAS  PubMed  Google Scholar 

  17. Yang, M. & Chen, P.R. Progress in the bioorthogonal labeling reactions. Acta Chim. Sinensis. 73, 783–792 (2015).

    CAS  Google Scholar 

  18. Spicer, C.D. & Davis, B.G. Selective chemical protein modification. Nat. Commun. 5, 4740 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Dawson, P.E., Muir, T., Clark-Lewis, I. & Kent, S. Synthesis of proteins by native chemical ligation. Science 266, 776–779 (1994).

    Article  CAS  PubMed  Google Scholar 

  20. Griffin, B.A., Adams, S.R. & Tsien, R.Y. Specific covalent labeling of recombinant protein molecules inside live cells. Science 281, 269–272 (1998).

    Article  CAS  PubMed  Google Scholar 

  21. Saxon, E. & Bertozzi, C.R. Cell surface engineering by a modified Staudinger reaction. Science 287, 2007–2010 (2000).

    Article  CAS  PubMed  Google Scholar 

  22. Hang, H.C., Yu, C., Kato, D.L. & Bertozzi, C.R. A metabolic labeling approach toward proteomic analysis of mucin-type O-linked glycosylation. Proc. Natl. Acad. Sci. USA 100, 14846–14851 (2003). This paper applied the Staudinger ligation reaction on living cells and was the first to use the term 'bioorthogonal chemistry'.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kolb, H.C., Finn, M.G. & Sharpless, K.B. Click chemistry: diverse chemical function from a few good reactions. Angew. Chem. Int. Ed. Engl. 40, 2004–2021 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Marczewska, J., Koziorowska, J.H. & Anuszewska, E.L. Influence of ascorbic acid on cytotoxic activity of copper and iron ions in vitro. Acta Pol. Pharm. 57, 415–418 (2000).

    CAS  PubMed  Google Scholar 

  25. Macomber, L. & Imlay, J.A. The iron-sulfur clusters of dehydratases are primary intracellular targets of copper toxicity. Proc. Natl. Acad. Sci. USA 106, 8344–8349 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Debets, M.F. et al. Bioconjugation with strained alkenes and alkynes. Acc. Chem. Res. 44, 805–815 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Sletten, E.M. & Bertozzi, C.R. From mechanism to mouse: a tale of two bioorthogonal reactions. Acc. Chem. Res. 44, 666–676 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Blackman, M.L., Royzen, M. & Fox, J.M. Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity. J. Am. Chem. Soc. 130, 13518–13519 (2008). A report of a highly efficient inverse electron-demand Diels-Alder reaction with an unprecedented reaction rate in living systems.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Devaraj, N.K. & Weissleder, R. Biomedical applications of tetrazine cycloadditions. Acc. Chem. Res. 44, 816–827 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Selvaraj, R. & Fox, J.M. trans-Cyclooctene—a stable, voracious dienophile for bioorthogonal labeling. Curr. Opin. Chem. Biol. 17, 753–760 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Soriano del Amo, D. et al. Biocompatible copper(I) catalysts for in vivo imaging of glycans. J. Am. Chem. Soc. 132, 16893–16899 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Yang, M. et al. Biocompatible click chemistry enabled compartment-specific pH measurement inside E. coli. Nat. Commun. 5, 4981 (2014).

    Article  CAS  PubMed  Google Scholar 

  33. Lin, Y.A., Chalker, J.M., Floyd, N., Bernardes, G.J.L. & Davis, B.G. Allyl sulfides are privileged substrates in aqueous cross-metathesis: application to site-selective protein modification. J. Am. Chem. Soc. 130, 9642–9643 (2008).

    Article  CAS  PubMed  Google Scholar 

  34. Chalker, J.M., Wood, C.S.C. & Davis, B.G. A convenient catalyst for aqueous and protein Suzuki-Miyaura cross-coupling. J. Am. Chem. Soc. 131, 16346–16347 (2009). This paper described the development of Pd-catalyzed cross-coupling reaction with biocompatible ligands for protein modifications.

    Article  CAS  PubMed  Google Scholar 

  35. Li, N., Lim, R.K.V., Edwardraja, S. & Lin, Q. Copper-free Sonogashira cross-coupling for functionalization of alkyne-encoded proteins in aqueous medium and in bacterial cells. J. Am. Chem. Soc. 133, 15316–15319 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Li, J. et al. Ligand-free palladium-mediated site-specific protein labeling inside gram-negative bacterial pathogens. J. Am. Chem. Soc. 135, 7330–7338 (2013).

    Article  CAS  PubMed  Google Scholar 

  37. Chankeshwara, S.V., Indrigo, E. & Bradley, M. Palladium-mediated chemistry in living cells. Curr. Opin. Chem. Biol. 21, 128–135 (2014).

    Article  CAS  PubMed  Google Scholar 

  38. Lim, R.K.V. & Lin, Q. Photoinducible bioorthogonal chemistry: a spatiotemporally controllable tool to visualize and perturb proteins in live cells. Acc. Chem. Res. 44, 828–839 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Sasmal, P.K., Streu, C.N. & Meggers, E. Metal complex catalysis in living biological systems. Chem. Commun. (Camb.) 49, 1581–1587 (2013).

    Article  CAS  Google Scholar 

  40. Völker, T. & Meggers, E. Transition-metal-mediated uncaging in living human cells—an emerging alternative to photolabile protecting groups. Curr. Opin. Chem. Biol. 25, 48–54 (2015).

    Article  PubMed  CAS  Google Scholar 

  41. Klán, P. et al. Photoremovable protecting groups in chemistry and biology: reaction mechanisms and efficacy. Chem. Rev. 113, 119–191 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Donato, L. et al. Water-soluble, donor-acceptor biphenyl derivatives in the 2-(o-nitrophenyl)propyl series: highly efficient two-photon uncaging of the neurotransmitter γ-aminobutyric acid at l=800 nm. Angew. Chem. Int. Ed. Engl. 51, 1840–1843 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Xu, J. et al. A rapid response “Turn-On” fluorescent probe for nitroreductase detection and its application in hypoxic tumor cell imaging. Analyst 140, 574–581 (2015).

    Article  CAS  PubMed  Google Scholar 

  44. Bae, J. et al. Nitroreductase-triggered activation of a novel caged fluorescent probe obtained from methylene blue. Chem. Commun. (Camb.) 51, 12787–12790 (2015).

    Article  CAS  Google Scholar 

  45. Streu, C. & Meggers, E. Ruthenium-induced allylcarbamate cleavage in living cells. Angew. Chem. Int. Ed. Engl. 45, 5645–5648 (2006). This study is one of the earliest examples of chemically mediated biocompatible cleavage reactions on small molecules inside living cells.

    Article  CAS  PubMed  Google Scholar 

  46. Völker, T., Dempwolff, F., Graumann, P.L. & Meggers, E. Progress towards bioorthogonal catalysis with organometallic compounds. Angew. Chem. Int. Ed. Engl. 53, 10536–10540 (2014).

    Article  PubMed  CAS  Google Scholar 

  47. Isidro-Llobet, A., Álvarez, M. & Albericio, F. Amino acid-protecting groups. Chem. Rev. 109, 2455–2504 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Yusop, R.M., Unciti-Broceta, A., Johansson, E.M.V., Sánchez-Martín, R.M. & Bradley, M. Palladium-mediated intracellular chemistry. Nat. Chem. 3, 239–243 (2011). This work first showed that palladium-mediated reactions could be employed inside living mammalian cells.

    Article  CAS  PubMed  Google Scholar 

  49. Li, J. et al. Palladium-triggered deprotection chemistry for protein activation in living cells. Nat. Chem. 6, 352–361 (2014). This study demonstrated that Pd-mediated bioorthogonal cleavage chemistry could be used to activate a protein of interest in living cells.

    Article  CAS  PubMed  Google Scholar 

  50. Weiss, J.T. et al. Development and bioorthogonal activation of palladium-labile prodrugs of gemcitabine. J. Med. Chem. 57, 5395–5404 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Kislukhin, A.A., Hong, V.P., Breitenkamp, K.E. & Finn, M.G. Relative performance of alkynes in copper-catalyzed azide-alkyne cycloaddition. Bioconjug. Chem. 24, 684–689 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Versteegen, R.M., Rossin, R., ten Hoeve, W., Janssen, H.M. & Robillard, M.S. Click to release: instantaneous doxorubicin elimination upon tetrazine ligation. Angew. Chem. Int. Ed. Engl. 52, 14112–14116 (2013).

    Article  CAS  PubMed  Google Scholar 

  53. Li, J., Jia, S. & Chen, P.R. Diels-Alder reaction–triggered bioorthogonal protein decaging in living cells. Nat. Chem. Biol. 10, 1003–1005 (2014). This work demonstrated a highly efficient bioorthogonal cleavage chemistry for protein activation in living systems.

    Article  CAS  PubMed  Google Scholar 

  54. Matikonda, S.S. et al. Bioorthogonal prodrug activation driven by a strain-promoted 1,3-dipolar cycloaddition. Chem. Sci. 6, 1212–1218 (2015).

    Article  CAS  PubMed  Google Scholar 

  55. Pawlak, J.B. et al. Bioorthogonal deprotection on the dendritic cell surface for chemical control of antigen cross-presentation. Angew. Chem. Int. Ed. Engl. 54, 5628–5631 (2015). This study utilized a bioorthogonal cleavage reactions to manipulate T cell activation.

    Article  CAS  PubMed  Google Scholar 

  56. Chen, Y., Kamlet, A.S., Steinman, J.B. & Liu, D.R. A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system. Nat. Chem. 3, 146–153 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Hu, C. & Chen, Y. Biomolecule-compatible chemical bond-formation and bond-cleavage reactions induced by visible light. Tetrahedr. Lett. 56, 884–888 (2015).

    Article  CAS  Google Scholar 

  58. Li, L. et al. A sensitive two-photon probe to selectively detect monoamine oxidase B activity in Parkinson's disease models. Nat. Commun. 5, 3276 (2014).

    Article  CAS  PubMed  Google Scholar 

  59. Ritter, C. et al. Bioorthogonal enzymatic activation of caged compounds. Angew. Chem. Int. Ed. Engl. 54, 13440–13443 (2015). This work developed a potentially powerful bioorthogonal enzymatic cleavage reaction through directed evolution.

    Article  CAS  PubMed  Google Scholar 

  60. Tian, L. et al. Selective esterase-ester pair for targeting small molecules with cellular specificity. Proc. Natl. Acad. Sci. USA 109, 4756–4761 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Marletta, M.A. Raising enzymes from the dead and the secrets they can tell. ACS Chem. Biol. 1, 73–74 (2006).

    Article  CAS  PubMed  Google Scholar 

  62. Zorn, J.A. & Wells, J.A. Turning enzymes ON with small molecules. Nat. Chem. Biol. 6, 179–188 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Qiao, Y., Molina, H., Pandey, A., Zhang, J. & Cole, P.A. Chemical rescue of a mutant enzyme in living cells. Science 311, 1293–1297 (2006).

    Article  CAS  PubMed  Google Scholar 

  64. Armbruster, B.N., Li, X., Pausch, M.H., Herlitze, S. & Roth, B.L. Evolving the lock to fit the key to create a family of G protein-coupled receptors potently activated by an inert ligand. Proc. Natl. Acad. Sci. USA 104, 5163–5168 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Baker, A.S. & Deiters, A. Optical control of protein function through unnatural amino acid mutagenesis and other optogenetic approaches. ACS Chem. Biol. 9, 1398–1407 (2014).

    Article  CAS  PubMed  Google Scholar 

  66. Chin, J.W. Expanding and reprogramming the genetic code of cells and animals. Annu. Rev. Biochem. 83, 379–408 (2014).

    Article  CAS  PubMed  Google Scholar 

  67. Liu, C.C. & Schultz, P.G. Adding new chemistries to the genetic code. Annu. Rev. Biochem. 79, 413–444 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Wan, W., Tharp, J.M. & Liu, W.R. Pyrrolysyl-tRNA synthetase: an ordinary enzyme but an outstanding genetic code expansion tool. Biochim. Biophys. Acta 1844, 1059–1070 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cui, J. & Shao, F. Biochemistry and cell signaling taught by bacterial effectors. Trends Biochem. Sci. 36, 532–540 (2011).

    Article  CAS  PubMed  Google Scholar 

  70. Li, H. et al. The phosphothreonine lyase activity of a bacterial Type III effector family. Science 315, 1000–1003 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Gautier, A., Deiters, A. & Chin, J.W. Light-activated kinases enable temporal dissection of signaling networks in living cells. J. Am. Chem. Soc. 133, 2124–2127 (2011). This study combined photo-decaging reaction with genetic code expansion technique for selective activation of a specific kinase in living cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Manning, G., Whyte, D.B., Martinez, R., Hunter, T. & Sudarsanam, S. The protein kinase complement of the human genome. Science 298, 1912–1934 (2002).

    Article  CAS  PubMed  Google Scholar 

  73. Schmelz, S. & Naismith, J.H. Adenylate-forming enzymes. Curr. Opin. Struct. Biol. 19, 666–671 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Wang, J. et al. Chemical remodeling of cell-surface sialic acids through a palladium-triggered bioorthogonal elimination reaction. Angew. Chem. Int. Ed. Engl. 54, 5364–5368 (2015).

    Article  CAS  PubMed  Google Scholar 

  75. Huttunen, K.M., Raunio, H. & Rautio, J. Prodrugs—from serendipity to rational design. Pharmacol. Rev. 63, 750–771 (2011).

    Article  CAS  PubMed  Google Scholar 

  76. Mahato, R., Tai, W. & Cheng, K. Prodrugs for improving tumor targetability and efficiency. Adv. Drug Deliv. Rev. 63, 659–670 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Weiss, J.T. et al. Extracellular palladium-catalysed dealkylation of 5-fluoro-1-propargyl-uracil as a bioorthogonally activated prodrug approach. Nat. Commun. 5, 3277 (2014). This paper demonstrated the novel concept of bioorthogonal prodrug activation through Pd-mediated deprotection.

    Article  PubMed  CAS  Google Scholar 

  78. Tonga, G.Y. et al. Supramolecular regulation of bioorthogonal catalysis in cells using nanoparticle-embedded transition metal catalysts. Nat. Chem. 7, 597–603 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Chan, J., Dodani, S.C. & Chang, C.J. Reaction-based small-molecule fluorescent probes for chemoselective bioimaging. Nat. Chem. 4, 973–984 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Garner, A.L. & Koide, K. Studies of a fluorogenic probe for palladium and platinum leading to a palladium-specific detection method. Chem. Comm., 86–88 (2009).

  81. Santra, M., Ko, S.-K., Shin, I. & Ahn, K.H. Fluorescent detection of palladium species with an O-propargylated fluorescein. Chem. Commun. (Camb.) 46, 3964–3966 (2010).

    Article  CAS  Google Scholar 

  82. Ke, B. et al. A fluorescent probe for rapid aqueous fluoride detection and cell imaging. Chem. Commun. (Camb.) 49, 2494–2496 (2013).

    Article  CAS  Google Scholar 

  83. Roy, A., Datar, A., Kand, D., Saha, T. & Talukdar, P. A fluorescent off-on NBD-probe for F-sensing: theoretical validation and experimental studies. Org. Biomol. Chem. 12, 2143–2149 (2014).

    Article  CAS  PubMed  Google Scholar 

  84. Sachdeva, A., Wang, K., Elliott, T. & Chin, J.W. Concerted, rapid, quantitative, and site-specific dual labeling of proteins. J. Am. Chem. Soc. 136, 7785–7788 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Li, Q., Dong, T., Liu, X. & Lei, X. A bioorthogonal ligation enabled by click cycloaddition of o-quinolinone quinone methide and vinyl thioether. J. Am. Chem. Soc. 135, 4996–4999 (2013).

    Article  CAS  PubMed  Google Scholar 

  86. Nikić, I. et al. Minimal tags for rapid dual-color live-cell labeling and super-resolution microscopy. Angew. Chem. Int. Ed. Engl. 53, 2245–2249 (2014).

    Article  CAS  PubMed  Google Scholar 

  87. Zhang, X. et al. Second generation TQ-ligation for cell organelle imaging. ACS Chem. Biol. 10, 1676–1683 (2015).

    Article  CAS  PubMed  Google Scholar 

  88. Karginov, A.V. et al. Dissecting motility signaling through activation of specific Src-effector complexes. Nat. Chem. Biol. 10, 286–290 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Chu, P.-H. et al. Engineered kinase activation reveals unique morphodynamic phenotypes and associated trafficking for Src family isoforms. Proc. Natl. Acad. Sci. USA 111, 12420–12425 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Valencia, A., Chardin, P., Wittinghofer, A. & Sander, C. The ras protein family: evolutionary tree and role of conserved amino acids. Biochemistry 30, 4637–4648 (1991).

    Article  CAS  PubMed  Google Scholar 

  91. Jiang, J., Lazarus, M.B., Pasquina, L., Sliz, P. & Walker, S. A neutral diphosphate mimic crosslinks the active site of human O-GlcNAc transferase. Nat. Chem. Biol. 8, 72–77 (2012).

    Article  CAS  Google Scholar 

  92. Patricelli, M.P. & Cravatt, B.F. Clarifying the catalytic roles of conserved residues in the amidase signature family. J. Biol. Chem. 275, 19177–19184 (2000).

    Article  CAS  PubMed  Google Scholar 

  93. Weiss, J.T., Carragher, N.O. & Unciti-Broceta, A. Palladium-mediated dealkylation of N-propargyl-floxuridine as a bioorthogonal oxygen-independent prodrug strategy. Sci. Rep. 5, 9329 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Chari, R.V.J., Miller, M.L. & Widdison, W.C. Antibody-drug conjugates: an emerging concept in cancer therapy. Angew. Chem. Int. Ed. Engl. 53, 3796–3827 (2014).

    Article  CAS  PubMed  Google Scholar 

  95. Kim, J. & Bertozzi, C.R. A bioorthogonal reaction of N-oxide and boron reagents. Angew. Chem. Int. Ed. Engl. 54, 15777–15781 (2015). This study, published while our manuscript is under review, reported another new type of bioorthogonal bond-cleavage reaction between N-oxide and boron reagents.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Our research interests in expanding the bioorthogonal chemistry toolkit have been generously supported by the National Natural Science Foundation of China (21225206, 21521003 and 21432002) and the National Basic Research Program of China (2012CB917301).

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P.R.C. and J.L. wrote the manuscript and prepared the figures.

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Correspondence to Peng R Chen.

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Li, J., Chen, P. Development and application of bond cleavage reactions in bioorthogonal chemistry. Nat Chem Biol 12, 129–137 (2016). https://doi.org/10.1038/nchembio.2024

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