Design of new derivatives of nitrone DEPMPO functionalized at C-4 for further specific applications in superoxide radical detection

Florence Chalier, Micaël Hardy, Olivier Ouari, A. Rockenbauer, Paul Tordo

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

(Chemical Equation Presented) 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 reduction of the nitro compound 1. (4R*,5S*)-4- HMDEPMPO was successfully separated from its minor diastereoisomer 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 perspectives for targeted delivery applications. A short study of the trapping behaviors of the (4R*,5S*)-isomer of these 4-HMDEPMPO analogues proved that they are as good as DEPMPO for detecting superoxide. For each isomer, only one diastereoisomer adduct was obtained, resulting from the addition of superoxide on the less hindered face of the nitrone, that is, trans to the phosphoryl group and the C-4 substituent. From spectra simulation and experiments in various solvents, we proved that ESR patterns of each adduct corresponded to the superimposed signals of two sets of conformers in a sufficiently slow chemical exchange to induce a widening and a dissymmetry of some of the signal lines. This phenomenon was drastically reduced when compared with that observed for DEPMPO superoxide and attributed to a similar chemical exchange, and it did not hamper spectrum assignment. Determination of the decay rate of the superoxide adduct of (4R*,5S*)-4-HMDEPMPO proved that it has a 25% longer half-life time than the superoxide adduct of DEPMPO.

Original languageEnglish
Pages (from-to)7886-7892
Number of pages7
JournalJournal of Organic Chemistry
Volume72
Issue number21
DOIs
Publication statusPublished - Oct 12 2007

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Superoxides
Derivatives
Isomers
Oxides
Nitro Compounds
Paramagnetic resonance
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nitrones
Pharmaceutical Preparations
Experiments
pyrroline

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  • Organic Chemistry

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Design of new derivatives of nitrone DEPMPO functionalized at C-4 for further specific applications in superoxide radical detection. / Chalier, Florence; Hardy, Micaël; Ouari, Olivier; Rockenbauer, A.; Tordo, Paul.

In: Journal of Organic Chemistry, Vol. 72, No. 21, 12.10.2007, p. 7886-7892.

Research output: Contribution to journalArticle

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abstract = "(Chemical Equation Presented) 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 reduction of the nitro compound 1. (4R*,5S*)-4- HMDEPMPO was successfully separated from its minor diastereoisomer 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 perspectives for targeted delivery applications. A short study of the trapping behaviors of the (4R*,5S*)-isomer of these 4-HMDEPMPO analogues proved that they are as good as DEPMPO for detecting superoxide. For each isomer, only one diastereoisomer adduct was obtained, resulting from the addition of superoxide on the less hindered face of the nitrone, that is, trans to the phosphoryl group and the C-4 substituent. From spectra simulation and experiments in various solvents, we proved that ESR patterns of each adduct corresponded to the superimposed signals of two sets of conformers in a sufficiently slow chemical exchange to induce a widening and a dissymmetry of some of the signal lines. This phenomenon was drastically reduced when compared with that observed for DEPMPO superoxide and attributed to a similar chemical exchange, and it did not hamper spectrum assignment. Determination of the decay rate of the superoxide adduct of (4R*,5S*)-4-HMDEPMPO proved that it has a 25{\%} longer half-life time than the superoxide adduct of DEPMPO.",
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