A Bioorthogonal Quadricyclane Ligation

Abstract

New additions to the bioorthogonal chemistry compendium can advance biological research by enabling multiplexed analysis of biomolecules in complex systems. Here we introduce the quadricyclane ligation, a new bioorthogonal reaction between the highly strained hydrocarbon quadricyclane and Ni bis(dithiolene) reagents. This reaction has a second-order rate constant of 0.25 M–1 s–1, on par with fast bioorthogonal reactions of azides, and proceeds readily in aqueous environments. Ni bis(dithiolene) probes selectively labeled quadricyclane-modified bovine serum albumin, even in the presence of cell lysate. We have demonstrated that the quadricyclane ligation is compatible with, and orthogonal to, strain-promoted azide–alkyne cycloaddition and oxime ligation chemistries by performing all three reactions in one pot on differentially functionalized protein substrates. The quadricyclane ligation joins a small but growing list of tools for the selective covalent modification of biomolecules.

Click Chemistry in Complex Mixtures: Bioorthogonal Bioconjugation

“…An alternative strain-promoted reaction involving the compact quadricyclane structure was recently reported by Sletten and Bertozzi (Sletten and Bertozzi, 2011a). In its initial form, the desired [2+2+2] cycloaddition was found to occur most productively with the π-system of a Ni-bis(dithiolene) complex (Figure 6C, rate constant = 0.25 M −1 s −1 ).…”

Facile and Stabile Linkages through Tyrosine: Bioconjugation Strategies with the Tyrosine-Click Reaction

“…In a second step, the introduced extrinsic functionalities are selectively reacted to form oximes/hydrazones,(1–12) Staudinger ligation products,(1–4, 13) triazole-Click products,(1–4, 14–18) or Diels-Alder,(1–4, 19–23) among others. (1–4, 24) In addition to chemical routes, extrinsic functional groups can be introduced into biomolecules via enzymatic modification,(1–5, 11, 12),(19–23) or genetic encoding. (1–4, 25–33) Thus extrinsic approaches involve a minimum of two modification steps of the biomolecule.…”

Selective RNA Versus DNA G‐Quadruplex Targeting by In Situ Click Chemistry

“…[1] These stringent requirements have rendered the development of click reactions particularly challenging. [2] More recently, the term click chemistry has referred to the 1,3-dipolar cycloaddition of alkynes and azides that is promoted at room temperature by various copper-and ruthenium-based catalysts. [3] This powerful reaction has found broad applications that span from material science to cell biology.…”