Bioorthogonal chemistries are widely used to image and profile biomolecules in their native environments. While many bioorthogonal reactions have been reported in recent years, most cannot be used inside cells owing to reagent instabilities. Additionally, there are very few reactions that can be used concurrently for multi-component labeling without significant cross-reactivity. To address these limitations, we are developing new bioorthogonal ligations with cyclopropenones and triarylphosphines. These motifs are stable in aqueous solutions and in physiological environments. We initially synthesized a panel of disubstituted cyclopropenones and identified scaffolds that are inert to thiols and other biological nucleophiles. These substituted cyclopropenones also react efficiently with a wide array of functionalized phosphines to form covalent adducts. Importantly, the cyclopropenone-phosphine ligation can be used in tandem with other popular bioorthogonal chemistries. We further synthesized a cyclopropenone amino acid that can be used for recombinant protein production and intracellular labeling applications. Based on the biocompatibility and unique reactivity of cyclopropenones and phosphines, we anticipate that these reagents will be broadly adopted for bioorthogonal labeling experiments.

Cyclopropenones are stable bioorthogonal chemical reporters

251st National Meeting (2016)

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