Electrochemical generation and reactivity of free radical redox intermediates from ortho- and meta-nitro substituted 1,4-dihydropyridines.
This paper reports a comprehensive study by cyclic voltammetry on the electrochemical characteristics and the reactivity of the one-electron reduction product from a series of nitro aryl 1,4-dihydropyridines in mixed and aprotic media. In addition, the effects of 1,4-DHP on the oxygen consumption of T. cruzi epimastigotes are reported. One-electron reduction products from 1,4-DHP derivatives significantly reacted with both thiol compounds and the nuclei acid bases, adenine and uracil. This reactivity was significantly higher than the natural decay of the radicals in mixed media. Based on these results the following tentative order of reactivity towards the xeno/endobiotics is as follows: cysteamine > glutathione > adenineuracil. Both the stability and the reactivity of the nitro radical anions electrochemically generated from 1,4-DHP showed a linear dependence with pH. The sensitivity to pH of the radicals derived from o-nitro substituted derivatives was significantly higher than m-nitro substituted derivatives. On the other hand, in all cases an increase of pH produced a significant decrease in the interaction rate constant. Interaction studies carried out in aprotic media did not show any reactivity of the radicals towards both thiol compounds and the nuclei acid bases, adenine and uracil. Therefore, we concluded that the interaction process requires certain proton activity in the media. All the tested 1,4-dihydropyridines inhibited the oxygen consumption by T. cruzi epimastigotes, Tulahuén strain. The drugs with higher electron-affinity produced greater inhibition than those with lower electron-affinity (i.e. nicardipine vs nifedipine).
Núñez-Vergara
L J
LJ
Laboratory of Bioelectrochemistry, Faculty of Chemical and Pharmaceutical Sciences, University of Chile, Santiago, Chile.
Ortiz
M E
ME
Bollo
S
S
Squella
J A
JA
D000818:Animals; D003543:Cysteamine / Q000737:chemistry; D004095:Dihydropyridines / Q000737:chemistry* / Q000494:pharmacology*; D004563:Electrochemistry / Q000379:methods; D005609:Free Radicals / Q000737:chemistry; D005978:Glutathione / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D009574:Nitro Compounds / Q000737:chemistry* / Q000494:pharmacology*; D010084:Oxidation-Reduction; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000378:metabolism
D004095:Dihydropyridines; D005609:Free Radicals; D009574:Nitro Compounds; D003543:Cysteamine; C038806:1,4-dihydropyridine; D005978:Glutathione