Computationally guided discovery of a reactive, hydrophilic trans-5-oxocene dienophile for bioorthogonal labeling.

Autor:	Lambert WD; Brown Laboratory, Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, USA. jmfox@udel.edu., Scinto SL; Brown Laboratory, Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, USA. jmfox@udel.edu., Dmitrenko O; Brown Laboratory, Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, USA. jmfox@udel.edu., Boyd SJ; Brown Laboratory, Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, USA. jmfox@udel.edu., Magboo R; Lotus Separations LLC, Newark, DE 19711, USA., Mehl RA; Department of Biochemistry and Biophysics, Oregon State University, Corvallis, Oregon 97331, USA., Chin JW; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK., Fox JM; Brown Laboratory, Department of Chemistry & Biochemistry, University of Delaware, Newark, Delaware 19716, USA. jmfox@udel.edu., Wallace S; Medical Research Council Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus, Cambridge CB2 0QH, UK and Institute of Quantitative Biology, Biochemistry and Biotechnology, School of Biological Sciences, University of Edinburgh, UK.
Jazyk:	angličtina
Zdroj:	Organic & biomolecular chemistry [Org Biomol Chem] 2017 Aug 09; Vol. 15 (31), pp. 6640-6644.
DOI:	10.1039/c7ob01707c
Abstrakt:	The use of organic chemistry principles and prediction techniques has enabled the development of new bioorthogonal reactions. As this "toolbox" expands to include new reaction manifolds and orthogonal reaction pairings, the continued development of existing reactions remains an important objective. This is particularly important in cellular imaging, where non-specific background fluorescence has been linked to the hydrophobicity of the bioorthogonal moiety. Here we report that trans-5-oxocene (oxoTCO) displays enhanced reactivity and hydrophilicity compared to trans-cyclooctene (TCO) in the tetrazine ligation reaction. Aided by ab initio calculations we show that the insertion of a single oxygen atom into the trans-cyclooctene (TCO) ring system is sufficient to impart aqueous solubility and also results in significant rate acceleration by increasing angle strain. We demonstrate the rapid and quantitative cycloaddition of oxoTCO using a water-soluble tetrazine derivative and a protein substrate containing a site-specific genetically encoded tetrazine moiety both in vitro and in vivo. We anticipate that oxoTCO will find use in studies where hydrophilicity and fast bioconjugation kinetics are paramount.
Databáze:	MEDLINE
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