New heteroaryl nitrones with spin trap properties: Identification of a 4-furoxanyl derivative with excellent properties to be used in biological systems.
A new series of heteroaryl nitrones, 1-7, bearing furoxanyl and thiadiazolyl moieties, were evaluated for their free radical-trapping properties. The physicochemical characterization by electron paramagnetic resonance (EPR) demonstrated its capability to trap and stabilize oxygen-, carbon-, sulfur-, and nitrogen-centered free radicals. The 4-furoxanyl nitrone 3 (FxBN), alpha(Z)-(3-methylfuroxan-4-yl)-N-tert-butylnitrone, showed appropriate solubility in aqueous solution and taking into account that this physicochemical property is very important for biological applications, we studied it deeply in terms of its trapping and kinetic behaviors. For this, kinetic studies of the hydroxyl adduct decay gave rate constants k(ST) of 1.22x10(10)dm(3)mol(-1)s(-1) and half-live up to 7200s at physiological pH, without any artifactual signals. The ability of FxBN to directly traps and stabilizes superoxide free radical, with a half-life of 1620s at physiological pH, was also demonstrated. Besides, FxBN-hydroxyl and -superoxide adducts exhibited distinct and characteristic EPR spectral patterns. Finally, we confirmed the ability of FxBN to act as spin trap in a specific biological system, that is, in the free radical production of experimental anti-trypanosomatid drugs using Trypanosoma cruzi microsomes as biological system. Moreover, previous observations of low FxBN toxicity transform it in a good candidate for in vivo spin trapping.
Barriga
Germán
G
Departamento de Química Inorgánica y Analítica, Facultad de Ciencias Químicas y Farmacéuticas, Universidad de Chile, Santiago, Chile.
Olea-Azar
Claudio
C
Norambuena
Ester
E
Castro
Ana
A
Porcal
Williams
W
Gerpe
Alejandra
A
González
Mercedes
M
Cerecetto
Hugo
H
D004578:Electron Spin Resonance Spectroscopy; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology*; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008826:Microbial Sensitivity Tests; D015394:Molecular Structure; D009589:Nitrogen Oxides / Q000737:chemistry / Q000494:pharmacology*; D012995:Solubility; D013237:Stereoisomerism; D014349:Trypanosoma cruzi / Q000187:drug effects*
D006571:Heterocyclic Compounds; D009589:Nitrogen Oxides; C015388:nitrones