Reactivity of 1,4-dihydropyridines toward SIN-1-derived peroxynitrite.
OBJECTIVE
To study the reactivity of C4-substituted 1,4-dihydropyridines (1,4-DHP), with either secondary or tertiary nitrogen in the dihydropyridine ring, toward SIN-1-derived peroxynitrite in aqueous media at pH 7.4.


METHODS
Reactivity was followed by changes in the absorptivity of the UV-Vis bands corresponding to 1,4-DHP. Gas Chromatography/ Mass Spectrometer (GC-MS) and Electron Paramagnetic Resonance (EPR) spin trap techniques were used to characterize the final product and the intermediates of the reaction, respectively.


RESULTS
1,4-DHPs significantly reacted toward peroxynitrite at varied rates, according to the calculated kinetic rate constants. By EPR spectroscopy, a carbon-centered radical from the 1,4-DHP was intercepted with N-tert-butylamine-alpha-phenylnitrone (PBN), as the intermediate for the reaction with peroxynitrite. Likewise, the oxidized derivative (i.e., the pyridine) was identified as the final product of the reaction by GC-MS. By using the technique of deuterium kinetic isotope effect, the participation of the hydrogen of the 1-position on the 1,4-DHP ring was shown not to be the rate-limiting step of the reaction.


CONCLUSIONS
The direct participation of the 1,4-DHP derivatives in the quenching of SIN-1-derived peroxynitrite has been demonstrated. Kinetic rate constant of tested 1,4-DHP toward peroxynitrite showed a direct relationship with the oxidation peak potential values; that is, compounds reacting faster were more easily oxidized.
López-Alarcón
C
C
Laboratory of Bioelectrochemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
Speisky
H
H
Squella
J A
JA
Olea-Azar
C
C
Camargo
C
C
Núñez-Vergara
Luis J
LJ
D003903:Deuterium; D004095:Dihydropyridines / Q000737:chemistry*; D004578:Electron Spin Resonance Spectroscopy; D008401:Gas Chromatography-Mass Spectrometry; D007202:Indicators and Reagents; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008981:Molsidomine / Q000031:analogs & derivatives* / Q000737:chemistry*; D010084:Oxidation-Reduction; D030421:Peroxynitrous Acid / Q000737:chemistry*; D012996:Solutions; D013055:Spectrophotometry, Infrared; D013056:Spectrophotometry, Ultraviolet; D017550:Spectroscopy, Fourier Transform Infrared
D004095:Dihydropyridines; D007202:Indicators and Reagents; D012996:Solutions; D030421:Peroxynitrous Acid; C002385:linsidomine; D003903:Deuterium; D008981:Molsidomine