Elsevier

Drug Discovery Today

Volume 8, Issue 24, 15 December 2003, Pages 1128-1137
Drug Discovery Today

Review
The growing impact of click chemistry on drug discovery

https://doi.org/10.1016/S1359-6446(03)02933-7Get rights and content

Abstract

Click chemistry is a modular approach that uses only the most practical and reliable chemical transformations. Its applications are increasingly found in all aspects of drug discovery, ranging from lead finding through combinatorial chemistry and target-templated in situ chemistry, to proteomics and DNA research, using bioconjugation reactions. The copper-(I)-catalyzed 1,2,3-triazole formation from azides and terminal acetylenes is a particularly powerful linking reaction, due to its high degree of dependability, complete specificity, and the bio-compatibility of the reactants. The triazole products are more than just passive linkers; they readily associate with biological targets, through hydrogen bonding and dipole interactions.

Section snippets

The click chemistry approach

Click chemistry serves as a guiding principle in the quest for function: the search must be restricted to molecules that are easy to make. Focusing on lead discovery, this strategy provides a means for the rapid exploration of the chemical universe. For lead optimization, it enables rapid SAR profiling, through generation of analog libraries. Click chemistry does not replace existing methods for drug discovery, but rather, it complements and extends them. It works well in conjunction with

Click chemistry and drug discovery

Click chemistry is being used increasingly in biomedical research, ranging from lead discovery and optimization, to tagging of biological systems, such as proteins, nucleotides and whole organisms. The potential of this approach is highlighted here, by reviewing several early applications.

Click chemistry and bioconjugation

In vivo and in vitro bioconjugation applications benefit from the unprecedented reliability of the copper-catalyzed azide–acetylene union, the inertness of the reactants under physiological conditions, and the mild reaction conditions.

Conclusions

In summary, click chemistry has proven to be a powerful tool in biomedical research, ranging from combinatorial chemistry and target-templated in situ chemistry for lead discovery, to bioconjugation strategies for proteomics and DNA research. Of the various click chemistry reactions that are available to us, the union of azides and acetylenes to give triazoles deserves special recognition. Azides and acetylenes are stable across a broad range of organic reaction conditions and in biological

Acknowledgements

We are grateful to our colleagues M.G. Finn, Valery Fokin and Paul Carlier for advice and helpful discussions. We also thank Pascale Marchot, Yves Bourne and Palmer Taylor for allowing us to include the X-ray crystallographic results on the AChE inhibitors before publication, and Chi-Huey Wong for giving permission to discuss the HIV-protease work. Many thanks also to Paul Richardson and Zhi-Cai Shi of Lexicon Pharmaceuticals for being among the pioneers of click chemistry.

References (64)

  • Huisgen, R. (1984) 1,3-Dipolar cycloaddition – introduction, survey, mechanism. In 1,3-Dipolar Cycloaddition Chemistry...
  • K.A. Jorgensen

    Catalytic asymmetric hetero-Diels-Alder reactions of carbonyl compounds and imines

    Angew. Chem. Int. Ed. Engl.

    (2000)
  • L.F. Tietze et al.

    Hetero Diels-Alder reactions in organic chemistry

    Top. Curr. Chem.

    (1997)
  • H.C. Kolb

    Catalytic asymmetric dihydroxylation

    Chem. Rev.

    (1994)
  • A.V. Gontcharov

    tert-Butylsulfonamide. A new nitrogen source for catalytic aminohydroxylation and aziridination of olefins

    Org. Lett.

    (1999)
  • E. Kühle

    One-hundred years of sulfenic acid chemistry. IIa. Oxidation, reduction, and addition reactions of sulfenyl halides

    Synthesis (Mass.)

    (1970)
  • M.R. Gholami et al.

    Hydrophobic effects in 1,3-dipolar cycloaddition of C,N-diphenylnitrone with Dibutyl fumarate in aqueous solutions

    J. Chem. Res.

    (1999)
  • L.V. Lee

    A potent and highly selective inhibitor of human a-1,3-Fucosyltransferase via click chemistry

    J. Am. Chem. Soc.

    (2003)
  • V.V. Rostovtsev

    A stepwise Huisgen cycloaddition process: copper(I)-catalyzed regioselective ‘ligation’ of azides and terminal alkynes

    Angew. Chem. Int. Ed. Engl.

    (2002)
  • C.W. Tornøe

    Peptidotriazoles on solid phase: 1, 2, 3-Triazoles by Regiospecific Copper(I)-catalyzed 1,3-Dipolar Cycloadditions of terminal Alkynes to Azides

    J. Org. Chem.

    (2002)
  • W.P. Purcell et al.

    Electronic and molecular structure of selected unsubstituted and dimethyl amides from measurements of electric moments and nuclear magnetic resonance

    J. Phys. Chem.

    (1967)
  • Kolb, H.C. (2001) Application of Click Chemistry to the generation of new chemical libraries for drug discovery. In...
  • Kolb, H.C. et al. (2003) Large scale synthesis of optically pure aziridines....
  • Kolb, H.C. et al. (2003) Modified safe and efficient process for the environmentally friendly synthesis of imidoesters...
  • Kolb, H.C. et al. (2003) Preparation of 1,2,3-triazole carboxylic acids from azides and β-ketoesters in the presence of...
  • Chen, Z. et al. (1999) Preparation of 3-aminoazetidines as building blocks for combinatorial libraries. WO...
  • Kolb, H.C. et al. (2000) Preparation of PPAR-(gamma) agonists as agents for the treatment of type II diabetes....
  • S. Löber

    Click linker: efficient and high-yielding synthesis of a new family of SPOS resins by 1,3-dipolar cycloaddition

    Org. Lett.

    (2003)
  • Harju, K. et al. (2003) Solid-phase synthesis of 1,2,3-triazoles via 1,3-dipolar cycloaddition. J. Comb. Chem, (in...
  • (2003) Carbohydrate-based Drug Discovery. (Wong, C.-H., ed.), pp. 980,...
  • M. Mammen

    Polyvalent interactions in biological systems: implications for design and use of multivalent ligands and inhibitors

    Angew. Chem. Int. Ed. Engl.

    (1998)
  • F. Perez-Balderas

    Multivalent neoglycoconjugates by regiospecific cycloaddition of alkynes and azides using organic-soluble copper catalysts

    Org. Lett.

    (2003)
  • Cited by (3021)

    View all citing articles on Scopus
    View full text