Synthesis, Structure and Impact of 5-Aminoorotic Acid and Its Complexes with Lanthanum(III) and Gallium(III) on the Activity of Xanthine Oxidase

The superoxide radical ion is involved in numerous physiological processes, associated with both health and pathology. Its participation in cancer onset and progression is well documented. Lanthanum(III) and gallium(III) are cations that are known to possess anticancer properties. Their coordination complexes are being investigated by the scientific community in the search for novel oncological disease remedies. Their complexes with 5-aminoorotic acid suppress superoxide, derived enzymatically from xanthine/xanthine oxidase (X/XO). It seems that they, to differing extents, impact the enzyme, or the substrate, or both. The present study closely examines their chemical structure by way of modern methods—IR, Raman, and 1H NMR spectroscopy. Their superoxide-scavenging behavior in the presence of a non-enzymatic source (potassium superoxide) is compared to that in the presence of an enzymatic source (X/XO). Enzymatic activity of XO, defined in terms of the production of uric acid, seems to be impacted by both complexes and the pure ligand in a concentration-dependent manner. In order to better relate the compounds’ chemical characteristics to XO inhibition, they were docked in silico to XO. A molecular docking assay provided further proof that 5-aminoorotic acid and its complexes with lanthanum(III) and gallium(III) very probably suppress superoxide production via XO inhibition.

Технології комплексоутворення в системі краун-етер – KO2 –розчинник, як один з методів отримання стабільної форми аніон-радикалу кисню

Study of reactions of obtaining anion-radical of oxygen: one-electron oxygen reduction and complex formation in the system of crown-ether - potassium superoxide - solvent. Investigation of the possibility of regulating the activity of two different supramolecular structures containing oxygen anion radical to create new antioxidant systems. The oxygen anion radical in solution was obtained by the method of electrochemical oxygen reduction, as well as by complexation in the system of crown ether – potassium superoxide – solvent. The amount of oxygen radical anion obtained was monitored spectrophotometrically using a high-quality reaction with tetrazolium blue and the potentiometric method using an exchange reaction with butyl bromide. The activity of two different supramolecular structures containing oxygen anion radical is compared. It is shown that in the transition from the chemical method of generation of oxygen anion radical to electrochemical, the activity of the anion radical in the reaction with alkyl halide increases slightly. Spectrophotometrically and potentiometrically determined the kinetic parameters of the electrochemical oxygen reduction in the aprotic medium, as well as the process of complexation in the system of crown ether – potassium superoxide – solvent. The activity of two different supramolecular structures containing anion-radical of oxygen with the (Crown-K)+ and (tetraethylammonium)+ ions in reaction with propyl bromide in acetonitrile was compared. The conducted studies allow us to choose the optimal mode and structure of the complex - the sources of oxygen anion radical, depending on the task and goals of the experiment. The study of the complexation reaction in the system of crown ethers - potassium superoxide - solvent, along with the electrochemical method of obtaining active oxygen, is necessary not only in terms of obtaining the most stable form of oxygen anion radical, but also the creation of model systems that allow to analyze the mechanisms and patterns of the processes in biological systems. The obtained results indicate the prospect of using the investigated supramolecular complexes containing oxygen anion radical to create new antioxidant systems that can be used as new classes of antioxidants for engineering, medicine and pharmacy purposes.

Charge transport mechanisms in potassium superoxide

The variable valence states of oxygen dimers are the key to the formation of small polarons that contribute to conductivity.

Repurposing of the Nootropic Drug Vinpocetine as an Analgesic and Anti-Inflammatory Agent: Evidence in a Mouse Model of Superoxide Anion-Triggered Inflammation

Clinically active drugs for the treatment of acute pain have their prescription limited due to the significant side effects they induce. An increase in reactive oxygen species (ROS) has been linked to several conditions, including inflammation and pain processing. Therefore, new or repurposed drugs with the ability of reducing ROS-triggered responses are promising candidates for analgesic drugs. Vinpocetine is a clinically used nootropic drug with antioxidant, anti-inflammatory, and analgesic properties. However, the effects of vinpocetine have not been investigated in a model with a direct relationship between ROS, inflammation, and pain. Based on that, we aimed to investigate the effects of vinpocetine in a model of superoxide anion-induced pain and inflammation using potassium superoxide (KO2) as a superoxide anion donor to trigger inflammation and pain. In the KO2 model, vinpocetine dose-dependently reduced pain-like behaviors (spontaneous pain and hyperalgesia), paw edema, and neutrophil and mononuclear cell recruitment to the paw skin (assessed by H&E staining, fluorescence, and enzymatic assays) and to the peritoneal cavity. Vinpocetine also restored tissue endogenous antioxidant ability and Nrf2 and Ho-1 mRNA expression and reduced superoxide anion production and gp91phox mRNA expression. We also observed the inhibition of IκBα degradation by vinpocetine, which demonstrates a reduction in the activation of NF-κB explaining the diminished production of IL-33, IL-1β, and TNF-α. Collectively, our data show that vinpocetine alleviates pain and inflammation induced by KO2, which is a mouse model with a direct role of ROS in triggering pain and other inflammatory phenomena. Thus, the results suggest the repurposing of vinpocetine as an anti-inflammatory and analgesic drug.