文摘
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A general synthetic route to prepare derivatives of the DEPMPO nitrone (5-diethoxyphosphoryl-5-methyl-1-pyrroline-N-oxide) functionalized at C-4 was established via the synthesis of 4-HMDEPMPO nitrone(5-diethoxyphosphoryl-4-hydroxymethyl-5-methyl-1-pyrroline-N-oxide) that was obtained from reductionof the nitro compound 1. (4R*,5S*)-4-HMDEPMPO was successfully separated from its minordiastereoisomer and could be used to generate various substituted analogues. Among them, 4-NHSDEPMPO, 5-diethoxyphosphoryl-4-succinimidyloxycarbonyloxymethyl-5-methyl-1-pyrroline-N-oxide, constitutes a NH2-reactive precursor for further conjugation to relevant moieties such as targeting groups,labels, or drugs. From 4-NHSDEPMPO, a biotinylated nitrone was synthesized offering new perspectivesfor targeted delivery applications. A short study of the trapping behaviors of the (4R*,5S*)-isomer ofthese 4-HMDEPMPO analogues proved that they are as good as DEPMPO for detecting superoxide. Foreach isomer, only one diastereoisomer adduct was obtained, resulting from the addition of superoxide onthe less hindered face of the nitrone, that is, trans to the phosphoryl group and the C-4 substituent. Fromspectra simulation and experiments in various solvents, we proved that ESR patterns of each adductcorresponded to the superimposed signals of two sets of conformers in a sufficiently slow chemicalexchange to induce a widening and a dissymmetry of some of the signal lines. This phenomenon wasdrastically reduced when compared with that observed for DEPMPO superoxide and attributed to a similarchemical exchange, and it did not hamper spectrum assignment. Determination of the decay rate of thesuperoxide adduct of (4R*,5S*)-4-HMDEPMPO proved that it has a 25% longer half-life time than thesuperoxide adduct of DEPMPO.
