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

Viacheslav V Andrianov ^{1, 2}

Igor A Schepetkin ^{3, 4}

Liya V Bazan ¹

Khalil L. Gainutdinov ^{1, 2}

Anastasia R Kovrizhina ³

Dmitriy N Atochin ⁵

Andrei I. Khlebnikov ³

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Zavoisky Physical-Technical Institute of the Russian Academy of Sciences, Kazan 420029, Russia |

Department of Human and Animal Physiology, Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia |

Kizhner Research Center, Tomsk Polytechnic University, Tomsk 634050, Russia |

⁴

Department of Microbiology and Cell Biology, Montana State University, Bozeman, MT 59717, USA |

⁵

Cardiovascular Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02115, USA

Publication type: Journal Article

Publication date: 2024-08-12

MDPI

Journal: Molecules

scimago Q1

SJR: 0.744

CiteScore: 7.4

Impact factor: 4.2

ISSN: 14203049

DOI: 10.3390/molecules29163820

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Abstract

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.