The first “ready-to-use” benzene-based heterotrifunctional cross-linker for multiple bioconjugation?

Organic & Biomolecular Chemistry Pub Date: 2013-02-14 DOI: 10.1039/C3OB40086G

Abstract

The synthesis and applications of the first water-soluble benzene derivative bearing a set of three different and orthogonal bioconjugatable groups (aminooxy, azido and thiol) are described. The combined use of a 5-amino isophthalic acid scaffold and unusual acid-labile protecting groups for temporarily masking aminooxy and thiol moieties has enabled the development of a highly convergent approach towards the synthesis of such a trivalent bioconjugation platform in good yields. The potential utility of this “ready-to-use” cross-linking reagent for creating complex and fragile tri-component (bio)molecular systems was illustrated through (1) the rapid preparation of a three-colour FRET cascade with valuable spectral properties and (2) the luminescent/fluorescent labelling of peptides and peptide–oligonucleotide conjugates. Thus, such (bio)molecular assemblies were readily obtained via a three-step process or in a “one-pot” manner, both involving oxime ligation, thiol-alkylation (SN2 or Michael addition) and copper-catalysed azide-alkyne 1,3-dipolar cycloaddition (CuAAC) reactions.

Graphical abstract: The first “ready-to-use” benzene-based heterotrifunctional cross-linker for multiple bioconjugation
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