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Angew Chem Int Ed Engl. 2014 Jun 2;53(23):5805-9. doi: 10.1002/anie.201400135. Epub 2014 Apr 24.

In situ synthesis of alkenyl tetrazines for highly fluorogenic bioorthogonal live-cell imaging probes.

Author information

1
Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093 (USA) http://devarajgroup.ucsd.edu/

Abstract

In spite of the wide application potential of 1,2,4,5-tetrazines, particularly in live-cell and in vivo imaging, a major limitation has been the lack of practical synthetic methods. Here we report the in situ synthesis of (E)-3-substituted 6-alkenyl-1,2,4,5-tetrazine derivatives through an elimination-Heck cascade reaction. By using this strategy, we provide 24 examples of π-conjugated tetrazine derivatives that can be conveniently prepared from tetrazine building blocks and related halides. These include tetrazine analogs of biological small molecules, highly conjugated buta-1,3-diene-substituted tetrazines, and a diverse array of fluorescent probes suitable for live-cell imaging. These highly conjugated probes show very strong fluorescence turn-on (up to 400-fold) when reacted with dienophiles such as cyclopropenes and trans-cyclooctenes, and we demonstrate their application for live-cell imaging. This work provides an efficient and practical synthetic methodology for tetrazine derivatives and will facilitate the application of conjugated tetrazines, particularly as fluorogenic probes for live-cell imaging.

KEYWORDS:

bioorthogonal reaction; cellular imaging; cycloaddition; fluorophores; heterocycles

PMID:
24764312
PMCID:
PMC4104127
DOI:
10.1002/anie.201400135
[Indexed for MEDLINE]
Free PMC Article

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