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Development of isoindoline nitroxides for EPR oximetry in viable systems

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Abstract

Nitroxides are widely used as biophysical probes to study molecular motion, intracellular oxygen, pH, transmembrane potential, and cellular redox metabolism, etc. They may be rapidly metabolized to hydroxylamines by cells, which limits their use in viable systems. In this study, we have characterized relevant properties in cells of several isoindoline nitroxides that have been prepared to have different physicochemical properties: 1,1,3,3-tetramethylisoindolin-2-yloxyl (TMIO) and its analogs 5-carboxy-1,1,3,3-tetramethylisoindolin-2-yloxyl (CTMIO), 5-(N,N,N-trimethylammonio)-1,1,3,3-tetramethyl isoindolin-2-yloxyl iodide (QATMIO) and 2-hydroxy-1,1,3,3-tetramethylisoindoline hydrochloride (TMIOH.HCI). The oxygen sensitivity and metabolic kinetics of these were compared in CHO cells under different oxygen tensions with 1-oxyl-2,2,6,6-tetramethyl-4-piperidione (Tempone) and 3-carboxyl-2,2,5,5-tetramethyl-pyrrolidine-1-oxyl (PCA). Cytotoxicity was evaluated by the measurement of oxygen consumption rates, trypan blue exclusion, and clone formation. TMIO and its analogues have a higher relative oxygen sensitivity than Tempone and PCA with the oxygen sensitivity in electron paramagnetic resonance (EPR) spectrometry in the order of: TMIO=TMIOH=CTMIO>QATMIO=Tempone<PCA. The rates of metabolism of these nitroxides are moderate and depend on oxygen concentration, ring type, ring substituent, and membrane permeation. These nitroxides have low cytotoxicity. The results indicate that TMIO and its analogues are potentially useful for EPR studies of viable systems, especially for oximetry.

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Authors and Affiliations

  1. EPR Center, Department of Diagnostic Radiology, Dartmouth Medical School, 03755, Hanover, NH, USA

    J. Shen, N. Khan, O. Grinberg & H. Swartz

  2. Center for Instrumental and Developmental Chemistry, Queensland University of Technology, Brisbane, Queensland, Australia

    S. Bottle, D. Reid & A. Micallef

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  1. J. Shen
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  2. S. Bottle
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  3. N. Khan
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  4. O. Grinberg
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  6. A. Micallef
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  7. H. Swartz
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Shen, J., Bottle, S., Khan, N. et al. Development of isoindoline nitroxides for EPR oximetry in viable systems. Appl. Magn. Reson. 22, 357–368 (2002). https://doi.org/10.1007/BF03166117

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  • DOI: https://doi.org/10.1007/BF03166117

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