Issue 23, 2019

Development of a self-immolative linker for tetrazine-triggered release of alcohols in cells

Abstract

Bioorthogonal decaging reactions are a promising strategy for prodrug activation because they involve bond cleavage to release a molecule of interest. The trans-cyclooctene (TCO)-tetrazine inverse electron-demand Diels–Alder reaction has been widely applied in vivo for decaging of amine prodrugs, however, the release of alcohol-containing bioactive compounds has been less well studied. Here, we report a TCO-carbamate benzyl ether self-immolative linker for the release of OH-molecules upon reaction with a tetrazine trigger. The benzyl ether linker proved to be highly stable and can rapidly liberate alcohols under physiological conditions upon reaction with tetrazines. The mechanism and decaging yield were systematically examined by fluorescence and HPLC analysis by using a fluorogenic TCO–benzyl ether-coumarin probe and different 3,6-substituted tetrazine derivatives. This study revealed that decaging occurs rapidly (t1/2 = 27 min) and the cycloaddition step happens within seconds (t1/2 = 7 s) with reaction rates of ≈100 M−1 s−1. Importantly, the reaction is compatible with living organisms as demonstrated by the decaging of a prodrug of the antibacterial compound triclosan in the presence of live E. Coli, that resulted in complete cell killing by action of the released “OH-active drug”. Overall, this work describes a new linker for masking alcohol functionality that can be rapidly reinstated through tetrazine-triggered decaging.

Graphical abstract: Development of a self-immolative linker for tetrazine-triggered release of alcohols in cells

Supplementary files

Article information

Article type
Paper
Submitted
16 Apr 2019
Accepted
21 May 2019
First published
21 May 2019

Org. Biomol. Chem., 2019,17, 5725-5730

Development of a self-immolative linker for tetrazine-triggered release of alcohols in cells

S. Davies, B. L. Oliveira and G. J. L. Bernardes, Org. Biomol. Chem., 2019, 17, 5725 DOI: 10.1039/C9OB01167F

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