Sydnone

Abstract: The discovery and exploration of bioorthogonal chemical reactions and the biosynthetic incorporation of their components into biomolecules for specific labelling is an important challenge. Here we describe the reaction of a phenyl sydnone 1,3-dipole with a bicyclononyne dipolarophile. This strain-promoted reaction proceeds without transition metal catalysis in aqueous buffer, at physiological temperature, and pressure with a rate comparable to that of other bioorthogonal reactions. We demonstrate the quantitative and specific labelling of a genetically encoded bicyclononyne with a sydnone fluorophore conjugate, demonstrating the utility of this approach for bioorthogonal protein labelling.

Abstract: An overview of the different heterocyclic NO-releasing compounds is given. Mesoionic heterocycles like sydnone imines are one example. This class is discussed on the synthesis and the mechanism of NO formation from Molsidomine and its first metabolite SIN-1. Furthermore, 1,2,3,4 oxatriazolium olates and imidates are presented in an example of the synthesis of GEA-3175. Heterocyclic N-oxides are another group of compounds capable of NO release under certain conditions. This class is discussed in the example of furoxane carboxamides like CAS-1609, and some SAR-data show the great impact of intramolecular hydrogen bridges on their in vitro activity. Each class of compounds requires different cofactors for NO release: sydnone imines need oxidants like oxygen, furoxanes are converted to NO via reaction with thioles.

Abstract: Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M−1 s−1. Most significantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously.