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. 2008 Oct 15;130(41):13518-9.
doi: 10.1021/ja8053805. Epub 2008 Sep 18.

Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity

Melissa L Blackman  1 , Maksim Royzen, Joseph M Fox
Affiliations

Tetrazine ligation: fast bioconjugation based on inverse-electron-demand Diels-Alder reactivity

Melissa L Blackman et al. J Am Chem Soc. .

Abstract

Described is a bioorthogonal reaction that proceeds with unusually fast reaction rates without need for catalysis: the cycloaddition of s-tetrazine and trans-cyclooctene derivatives. The reactions tolerate a broad range of functionality and proceed in high yield in organic solvents, water, cell media, or cell lysate. The rate of the ligation between trans-cyclooctene and 3,6-di-(2-pyridyl)-s-tetrazine is very rapid (k2 2000 M-1 s-1). This fast reactivity enables protein modification at low concentration.

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Figures

Figure 1
Figure 1
(a) Rapid reactivity to form 12 was monitored by ESI-MS and HPLC. (b,c) Crude ESI-MS data for 11 and 12 in experiments that began with 15 μM Trx.
Scheme 1
Scheme 1
Diels-Alder reactions of tetrazines with trans-cyclooctene
Scheme 2
Scheme 2
Fast reactivity at low micromolar concentrations
Scheme 3
Scheme 3
Synthesis of trans-cyclooctene and tetrazine derivatives
See this image and copyright information in PMC

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