Conformational tuning improves the stability of spirocyclic nitroxides with long paramagnetic relaxation times



Nitroxides are widely used as probes and polarization transfer agents in spectroscopy and imaging. These applications require high stability towards reducing biological environments, as well as beneficial relaxation properties. While the latter is provided by spirocyclic groups on the nitroxide scaffold, such systems are not in themselves robust under reducing conditions. In this work, we introduce a strategy for stability enhancement through conformational tuning, where incorporating additional substituents on the nitroxide ring effects a shift towards highly stable closed spirocyclic conformations, as indicated by X-ray crystallography and DFT calculations. Closed spirocyclohexyl nitroxides exhibit a dramatically improved stability towards reduction by ascorbate, while maintaining long relaxation times in EPR spectroscopy. These findings have important implications for the future design of new nitroxide-based spin labels and imaging agents.


Supplementary material

Supporting Information
Experimental details and procedures, compound characterisation, NMR and EPR data, details of kinetic data processing, details of computational studies.

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Raw data
Raw data, including NMR and EPR spectra and kinetics studies.