1,2,4-Triazines Are Versatile Bioorthogonal Reagents

Abstract

A new class of bioorthogonal reagents, 1,2,4-triazines, is described. These scaffolds are stable in biological media and capable of robust reactivity with trans-cyclooctene (TCO). The enhanced stability of the triazine scaffold enabled its direct use in recombinant protein production. The triazine-TCO reaction can also be used in tandem with other bioorthogonal cycloaddition reactions. These features fill current voids in the bioorthogonal toolkit.

Exploring the Condensation Reaction between Aromatic Nitriles and Amino Thiols To Optimize In Situ Nanoparticle Formation for the Imaging of Proteases and Glycosidases in Cells

“…These reactions have been applied to site‐directed protein labeling, studying metabolic pathways, and engineering biomaterials . The applicability of these reactions to live systems is however often compromised by issues like insufficient stability or suboptimal reaction rates –. For example, some of the most reactive tetrazines have been found to be prone to hydrolysis and intracellular cysteine attack .…”

“…The applicability of these reactions to live systems is however often compromised by issues like insufficient stability or suboptimal reaction rates –. For example, some of the most reactive tetrazines have been found to be prone to hydrolysis and intracellular cysteine attack . The use of large hydrophobic moieties such as cyclooctyne to improve the reactivity also increases the potential for nonspecific binding to membrane structures .…”

1,3-Dipolar Cycloaddition Reactions of Low-Valent Rhodium and Iridium Complexes with Arylnitrile N-Oxides

“…2 Interest in these reactions has exploded, because of their many uses including biological applications. 3,4 The mechanisms of 1,3-dipolar cycloadditions have been extensively studied computationally, including the metal catalyzed variants. 5–7 Nitrile oxides undergo cycloadditions with alkenes, alkynes, and carbon-heteroatom multiple bonds.…”

John D. Roberts, his beginnings at UCLA, his transformation of physical organic chemistry, and his impact on science

“…These predictions are used for the development of bioorthogonal reactions—an example shown here from our collaborator, Jennifer Prescher . A protein labeled with this reactive triazine (Figure is not to scale!)…”

“…Illustration of using the cycloaddition of 1,2,4‐triazine (in an unnatural amino acid incorporated into green fluorescent protein) and trans ‐cyclooctene to probe biomolecules…”