Dendrimeric-Containing Nitronyl Nitroxides as Spin Traps for Nitric Oxide: Synthesis, Kinetic, and Stability Studies

Abstract

The in-vivo in-situ spin-trapping of NO• with iron chelates is limited in its ability to localize NO• at defined cellular compartments. Nitronyl nitroxides, such as 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline 3-oxide 1-oxyl, have been found to react with NO•. The resulting nitroxide, 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazolidine 1-oxyl, exhibits an EPR spectrum that is characteristically distinct from the parent nitroxide. However, nitronyl nitroxides are unstable in biologic milieu. This limits their ability to in vivo identify NO• at specific tissue compartments. Herein, we report on the preparation of a family of dendrimer-containing nitronyl nitroxides, which were developed to spin-trap NO•. Once synthesized, we determined their rate of reaction with NO• and their capacity to spin-trap NO• and estimated the stability of dendrimer-linked nitronyl nitroxides under various experimental paradigms. For the largest of the dendrimeric nitronyl nitroxides prepared, the reaction with NO• changed the EPR spectrum from one that was broad to that with a major component with narrow and defined spectral lines. These compounds promise to be excellent biological spin-trapping agents for NO•.