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, 130 (41), 13518-9

Tetrazine Ligation: Fast Bioconjugation Based on Inverse-Electron-Demand Diels-Alder Reactivity

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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.

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

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