Evaluation of Nitric Oxide-Donating Properties of 11H-indeno[1,2-b]quinoxalin-11-one Oxime (IQ-1) by Electron Paramagnetic Resonance Spectroscopy

• Published in: Molecules (Basel, Switzerland) Switzerland), 2024-08, Vol.29 (16), p.3820
• Main Authors: Andrianov, Viacheslav V., Schepetkin, Igor A., Bazan, Leah V., Gainutdinov, Khalil L., Kovrizhina, Anastasia R., Atochin, Dmitriy N., Khlebnikov, Andrei I.
• Format: Article
• Language: English
• Subjects: c-Jun N-terminal kinase (JNK) inhibitor; electron paramagnetic resonance; Hemoglobin; IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime); Ischemia; Ligands; Liver; Nitric oxide; nitric oxide donor; Oxidation; Spectrum analysis; spin trap; Traumatic brain injury
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules29163820

IQ-1 (11H-indeno[1,2-b]quinoxalin-11-one oxime) is a specific c-Jun N-terminal kinase (JNK) inhibitor with anticancer and neuro- and cardioprotective properties. Because aryloxime derivatives undergo cytochrome P450-catalyzed oxidation to nitric oxide (NO) and ketones in liver microsomes, NO formation may be an additional mechanism of IQ-1 pharmacological action. In the present study, electron paramagnetic resonance (EPR) of the Fe2+ complex with diethyldithiocarbamate (DETC) as a spin trap and hemoglobin (Hb) was used to detect NO formation from IQ-1 in the liver and blood of rats, respectively, after IQ-1 intraperitoneal administration (50 mg/kg). Introducing the spin trap and IQ-1 led to signal characteristics of the complex (DETC)2-Fe2+-NO in rat liver. Similarly, the introduction of the spin trap components and IQ-1 resulted in an increase in the Hb-NO signal for both the R- and the T-conformers in blood samples. The density functional theory (DFT) calculations were in accordance with the experimental data and indicated that the NO formation of IQ-1 through the action of superoxide anion radical is thermodynamically favorable. We conclude that the administration of IQ-1 releases NO during its oxidoreductive bioconversion in vivo.