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Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

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Abstract

In vivo compatible reactions have a broad range of possible applications in chemical biology and the pharmaceutical sciences. Here we report tetrazines that can be removed by exposure to isonitriles under very mild conditions. Tetrazylmethyl derivatives are easily accessible protecting groups for amines and phenols. The isonitrile-induced removal is rapid and near-quantitative. Intriguingly, the deprotection is especially effective with (trimethylsilyl)methyl isocyanide, and serum albumin can catalyze the elimination under physiological conditions. NMR and computational studies revealed that an imine-tautomerization step is often rate limiting, and the unexpected cleavage of the Si–C bond accelerates this step in the case with (trimethylsilyl)methyl isocyanide. Tetrazylmethyl-removal is compatible with use on biomacromolecules, in cellular environments, and in living organisms as demonstrated by cytotoxicity experiments and fluorophore-release studies on proteins and in zebrafish embryos. By combining tetrazylmethyl derivatives with previously reported tetrazine-responsive 3-isocyanopropyl groups, it was possible to liberate two fluorophores in vertebrates from a single bioorthogonal reaction. This chemistry will open new opportunities towards applications involving multiplexed release schemes and is a valuable asset to the growing toolbox of bioorthogonal dissociative reactions.

Graphical abstract: Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

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Publication details

The article was received on 14 Sep 2019, accepted on 05 Nov 2019 and first published on 05 Nov 2019


Article type: Edge Article
DOI: 10.1039/C9SC04649F
Chem. Sci., 2020, Advance Article
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    Isonitrile-responsive and bioorthogonally removable tetrazine protecting groups

    J. Tu, D. Svatunek, S. Parvez, H. J. Eckvahl, M. Xu, R. T. Peterson, K. N. Houk and R. M. Franzini, Chem. Sci., 2020, Advance Article , DOI: 10.1039/C9SC04649F

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