Synthesis and characterization of EMPO-derived 5,5-disubstituted 1-pyrroline N-oxides as spin traps forming exceptionally stable superoxide spin adducts.
EMPO [5-(ethoxycarbonyl)-5-methyl-1-pyrroline N-oxide] is a highly hydrophilic cyclic nitrone spin trap, whose superoxide adduct is considerably more stable (t 1/2 = 8.6 min) than DMPO (5,5-dimethyl-1-pyrroline N-oxide, t 1/2=45 s). EPR spectra of spin adducts of EMPO and its derivatives are very similar to those of the respective DMPO spin adducts, in contrast to the rather complex spectra obtained using DEPMPO [5-(diethoxyphosphoryl)-5-methyl-1-pyrroline N-oxide]. Several EMPO derivatives, with both the ethoxycarbonyl group and the methyl group at position 5 of the pyrroline ring being replaced by other substituents, were synthesized and characterized by 1H and 13C NMR spectroscopy. Thus, a series of derivatives was obtained that exhibit large differences in the stability of their superoxide adducts, ranging from less than one to more than 25 min. The stability of the superoxide adducts was mainly determined by the steric environment of the nitroxyl group: in compounds with less bulky 5-alkoxycarbonyl substituents the nitroxyl group is sterically less shielded, which resulted in a lower stability of the superoxide adducts. The spin density distribution, as obtained from DFT computations, was found to be nearly identical for all compounds, so that in contrast to the steric influences the spin density did not seem to be a crucial factor for the stability of the superoxide adducts.
Stolze
Klaus
K
Basic Pharmacology and Toxicology, University of Veterinary Medicine Vienna, Veterinärplatz 1, A-1210 Vienna, Austria.
Udilova
Natascha
N
Rosenau
Thomas
T
Hofinger
Andreas
A
Nohl
Hans
H
D003497:Cyclic N-Oxides / Q000138:chemical synthesis* / Q000737:chemistry; D004355:Drug Stability; D017665:Hydroxyl Radical / Q000737:chemistry; D015394:Molecular Structure; D019097:Spin Trapping; D013329:Structure-Activity Relationship; D013481:Superoxides / Q000737:chemistry*
C408629:5-ethoxycarbonyl-5-methyl-1-pyrroline N-oxide; D003497:Cyclic N-Oxides; D013481:Superoxides; D017665:Hydroxyl Radical