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A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system

Abstract

Using a system that accelerates the serendipitous discovery of new reactions by evaluating hundreds of DNA-encoded substrate combinations in a single experiment, we explored a broad range of reaction conditions for new bond-forming reactions. We discovered reactivity that led to a biomolecule-compatible, Ru(II)-catalysed azide-reduction reaction induced by visible light. In contrast to current azide-reduction methods, this reaction is highly chemoselective and is compatible with alcohols, phenols, acids, alkenes, alkynes, aldehydes, alkyl halides, alkyl mesylates and disulfides. The remarkable functional group compatibility and mild conditions of the reaction enabled the azide reduction of nucleic acid and oligosaccharide substrates, with no detectable occurrence of side reactions. The reaction was also performed in the presence of a protein enzyme without the loss of enzymatic activity, in contrast to two commonly used azide-reduction methods. The visible-light dependence of this reaction provides a means of photouncaging functional groups, such as amines and carboxylates, on biological macromolecules without using ultraviolet irradiation.

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Figure 1: DNA-encoded reaction-discovery system and validation experiments.
Figure 2: Selection results from four reaction conditions.
Figure 3: Development of the Ru(bpy)3Cl2-mediated azide-reduction reaction induced by visible light.
Figure 4: Compatibility of the azide-reduction reaction with biological molecules.

References

  1. Kanan, M. W., Rozenman, M. M., Sakurai, K., Snyder, T. M. & Liu, D. R. Reaction discovery enabled by DNA-templated synthesis and in vitro selection. Nature 431, 545–549 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  2. Beeler, A. B., Su, S., Singleton, C. A. & Porco, J. A. Discovery of chemical reactions through multidimensional screening. J. Am. Chem. Soc. 129, 1413–1419 (2007).

    CAS  PubMed  Google Scholar 

  3. Rozenman, M. M., Kanan, M. W. & Liu, D. R. Development and initial application of a hybridization-independent, DNA-encoded reaction discovery system compatible with organic solvents. J. Am. Chem. Soc. 129, 14933–14938 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  4. Scriven, E. F. V. & Turnbull, K. Azides – their preparation and synthetic uses. Chem. Rev. 88, 297–368 (1988).

    CAS  Google Scholar 

  5. Johnstone, R. A. W., Wilby, A. H. & Entwistle, I. D. Heterogeneous catalytic transfer hydrogenation and its relation to other methods for reduction of organic compounds. Chem. Rev. 85, 129–170 (1985).

    CAS  Google Scholar 

  6. Bayley, H., Standring, D. N. & Knowles, J. R. Propane-1,3-dithiol – selective reagent for efficient reduction of alkyl and aryl azides to amines. Tetrahedron Lett. 19, 3633–3634 (1978).

    Google Scholar 

  7. Gololobov, Y. G. & Kasukhin, L. F. Recent advances in the Staudinger reaction. Tetrahedron 48, 1353–1406 (1992).

    CAS  Google Scholar 

  8. Burns, J. A., Butler, J. C., Moran, J. & Whitesides, G. M. Selective reduction of disulfides by tris(2-carboxyethyl)phosphine. J. Org. Chem. 56, 2648–2650 (1991).

    CAS  Google Scholar 

  9. Maryanoff, B. E. & Reitz, A. B. The Wittig olefination reaction and modifications involving phosphoryl-stabilized carbanions – stereochemistry, mechanism, and selected synthetic aspects. Chem. Rev. 89, 863–927 (1989).

    CAS  Google Scholar 

  10. Sakurai, K., Snyder, T. M. & Liu, D. R. DNA-templated functional group transformations enable sequence-programmed synthesis using small-molecule reagents. J. Am. Chem. Soc. 127, 1660–1661 (2005).

    CAS  PubMed  Google Scholar 

  11. Agard, N. J., Baskin, J. M., Prescher, J. A., Lo, A. & Bertozzi, C. R. A comparative study of bioorthogonal reactions with azides. ACS Chem. Biol. 1, 644–648 (2006).

    CAS  PubMed  Google Scholar 

  12. Brase, S., Gil, C., Knepper, K. & Zimmermann, V. Organic azides: an exploding diversity of a unique class of compounds. Angew. Chem. Int. Ed. 44, 5188–5240 (2005).

    CAS  Google Scholar 

  13. Kohn, M. & Breinbauer, R. The Staudinger ligation – a gift to chemical biology. Angew. Chem. Int. Ed. 43, 3106–3116 (2004).

    Google Scholar 

  14. Kolb, H. C. & Sharpless, K. B. The growing impact of click chemistry on drug discovery. Drug Discov. Today 8, 1128–1137 (2003).

    CAS  PubMed  Google Scholar 

  15. Valeur, E. & Bradley, M. Amide bond formation: beyond the myth of coupling reagents. Chem. Soc. Rev. 38, 606–631 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  Google Scholar 

  17. Hermanson, G. T. Bioconjugate Techniques. 2nd edn, 169–181 (Academic, 2008).

    Google Scholar 

  18. Basle, E., Joubert, N. & Pucheault, M. Protein chemical modification on endogenous amino acids. Chem. Biol. 17, 213–227 (2010).

    CAS  PubMed  Google Scholar 

  19. Meldal, M. & Tornoe, C. W. Cu-catalyzed azide–alkyne cycloaddition. Chem. Rev. 108, 2952–3015 (2008).

    CAS  PubMed  Google Scholar 

  20. Holmberg, A. et al. The biotin–streptavidin interaction can be reversibly broken using water at elevated temperatures. Electrophoresis 26, 501–510 (2005).

    CAS  PubMed  Google Scholar 

  21. Solabannavar, S. B., Helavi, V. B., Desai, U. V. & Mane, R. B. A novel short synthesis of norbisabolide. Tetrahedron Lett. 43, 4535–4536 (2002).

    CAS  Google Scholar 

  22. Baciocchi, E., Dellaira, D. & Ruzziconi, R. Dimethyl arylmalonates from cerium(IV) ammonium-nitrate promoted reactions of dimethyl malonate with aromatic compounds in methanol. Tetrahedron Lett. 27, 2763–2766 (1986).

    CAS  Google Scholar 

  23. Poulsen, T. B. & Jorgensen, K. A. Catalytic asymmetric Friedel–Crafts alkylation reactions – copper showed the way. Chem. Rev. 108, 2903–2915 (2008).

    CAS  PubMed  Google Scholar 

  24. Bandini, M., Melloni, A. & Umani-Ronchi, A. New catalytic approaches in the stereoselective Friedel–Crafts alkylation reaction. Angew. Chem. Int. Ed. 43, 550–556 (2004).

    CAS  Google Scholar 

  25. Scheiner, P., Schomake, J. H., Deming, S., Libbey, W. J. & Nowack, G. P. Addition of aryl azides to norbornene. A kinetic investigation. J. Am. Chem. Soc. 87, 306–311 (1965).

    CAS  Google Scholar 

  26. Zhdankin, V. V. & Stang, P. J. Chemistry of polyvalent iodine. Chem. Rev. 108, 5299–5358 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Juris, A. et al. Ru(II) polypyridine complexes: photophysics, photochemistry, electrochemistry, and chemiluminescence. Coord. Chem. Rev. 84, 85–277 (1988).

    CAS  Google Scholar 

  28. Kalyanasundaram, K. Photophysics, photochemistry and solar-energy conversion with tris(bipyridyl)ruthenium(II) and its analogs. Coord. Chem. Rev. 46, 159–244 (1982).

    CAS  Google Scholar 

  29. Nicewicz, D. A. & MacMillan, D. W. C. Merging photoredox catalysis with organocatalysis: The direct asymmetric alkylation of aldehydes. Science 322, 77–80 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Ischay, M. A., Anzovino, M. E., Du, J. & Yoon, T. P. Efficient visible light photocatalysis of [2+2] enone cycloadditions. J. Am. Chem. Soc. 130, 12886–12887 (2008).

    CAS  PubMed  Google Scholar 

  31. Narayanam, J. M. R., Tucker, J. W. & Stephenson, C. R. J. Electron-transfer photoredox catalysis: development of a tin-free reductive dehalogenatioin reaction. J. Am. Chem. Soc. 131, 8756–8757 (2009).

    CAS  PubMed  Google Scholar 

  32. Yoon, T. P., Ischay, M. A. & Du, J. N. Visible light photocatalysis as a greener approach to photochemical synthesis. Nature Chem. 2, 527–532 (2010).

    CAS  Google Scholar 

  33. Delaive, P. J., Sullivan, B. P., Meyer, T. J. & Whitten, D. G. Applications of light-induced electron-transfer reactions – coupling of hydrogen generation with photo-reduction of ruthenium(II) complexes by triethylamine. J. Am. Chem. Soc. 101, 4007–4008 (1979).

    CAS  Google Scholar 

  34. Su, W., Li, Y. S. & Zhang, Y. M. Samarium diiodide induced reductive coupling of nitriles with azides. J. Chem. Res. (S), 32–33 (2001).

  35. Benati, L. et al. Radical reduction of aromatic azides to amines with triethylsilane. J. Org. Chem. 71, 5822–5825 (2006).

    CAS  PubMed  Google Scholar 

  36. Hays, D. S. & Fu, G. C. Development of Bu3SnH-catalyzed processes: efficient reduction of azides to amines. J. Org. Chem. 63, 2796–2797 (1998).

    CAS  Google Scholar 

  37. Borak, J. B. & Falvey, D. E. A new photolabile protecting group for release of carboxylic acids by visible-light-induced direct and mediated electron transfer. J. Org. Chem. 74, 3894–3899 (2009).

    CAS  PubMed  Google Scholar 

  38. Fancy, D. A. & Kodadek, T. Chemistry for the analysis of protein–protein interactions: rapid and efficient cross-linking triggered by long wavelength light. Proc. Natl Acad. Sci. USA 96, 6020–6024 (1999).

    CAS  PubMed  Google Scholar 

  39. Gill, M. R. et al. A ruthenium(II) polypyridyl complex for direct imaging of DNA structure in living cells. Nature Chem. 1, 662–667 (2009).

    CAS  Google Scholar 

  40. Raines, R. T. Ribonuclease A. Chem. Rev. 98, 1045–1065 (1998).

    CAS  PubMed  Google Scholar 

  41. Lee, H. M., Larson, D. R. & Lawrence, D. S. Illuminating the chemistry of life: design, synthesis, and applications of ‘caged’ and related photoresponsive compounds. ACS Chem. Biol. 4, 409–427 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Mayer, G. & Heckel, A. Biologically active molecules with a ‘light switch’. Angew. Chem. Int. Ed. 45, 4900–4921 (2006).

    CAS  Google Scholar 

  43. Sinha, R. P. & Hader, D. P. UV-induced DNA damage and repair: a review. Photochem. Photobiol. Sci. 1, 225–236 (2002).

    CAS  PubMed  Google Scholar 

  44. Griffin, R. J. et al. The 4-azidoberazyloxycarbonyl function; application as a novel protecting group and potential prodrug modification for amines. J. Chem. Soc. Perkin Trans. 1, 1205–1211 (1996).

  45. Wuts, P. G. M. & Greene, T. W. Greene's Protective Groups in Organic Synthesis. 4th edn, 533–646 (Wiley, 2007).

    Google Scholar 

  46. Crook, E. M., Mathias, A. P. & Rabin, B. R. Spectrophotometric assay of bovine pancreatic ribonuclease by the use of cytidine 2′-3′-phosphate. Biochem. J. 74, 234–238 (1960).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by NIH grant R01GM065865 and the Howard Hughes Medical Institute. We thank Y. Shen and C. Dumelin for MS assistance, and D. Gorin for discussions.

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Y.C., A.S.K., J.B.S. and D.R.L. designed the research, analysed the data and co-wrote the manuscript, Y.C., A.S.K. and J.B.S. performed the experiments.

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Correspondence to David R. Liu.

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Chen, Y., Kamlet, A., Steinman, J. et al. A biomolecule-compatible visible-light-induced azide reduction from a DNA-encoded reaction-discovery system. Nature Chem 3, 146–153 (2011). https://doi.org/10.1038/nchem.932

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