Balakina A. A.,Amozova V. I.,Stupina T. S.,Mumyatova V. A.,Podgurskaya A. D.,Gadomsky S. Ya.
A new method for the synthesis of pyridoxine salts with dicarboxylic acids was proposed. The specific features of the synthesis include the preliminary generation of free pyridoxine from the hydrochloride form by treatment with a solution of triethylamine in chloroform and conduction of the reaction of pyridoxine with dicarboxylic acid in a specially selected solvent mixture. The combination of pyridoxine as a known antioxidant and fumarate as an activator of the transcription factor Nrf2 in one molecule gave rise to a unique structure, bis[3-hydroxy-4,5-bis(hydroxymethyl)-2-methylpyridinium] fumarate (DPNF). In vitro experiments showed the ability of this compound to bind superoxide, suppress lipid peroxidation processes, and behave as a mitochondrial cytoprotective agent and Nrf2 activator. The results of the study can be used to develop a new type of drugs based on activators of the transcription factor Nrf2 to protect cells and tissues from oxidative damage.
Oxidative stress is constantly involved in the etiopathogenesis of an ever-widening range of neurodegenerative diseases. As a consequence, effective repression of cellular oxidative stress to a redox homeostatic condition is a promising and feasible strategy to treat, or at least retard the progression of, such disorders. Nrf2, a primary orchestrator of cellular antioxidant response machine, is responsible for detoxifying and compensating for deleterious oxidative stress via transcriptional activation of a diverse array of antioxidant biomolecules. In the framework of our persistent interest in disclosing small molecules that interfere with cellular redox-regulating machinery, we report herein the synthesis, optimization, and biological assessment of 47 vinyl sulfone scaffold-bearing small molecules, most of which exhibit robust neuroprotective effect against H 2 O 2 -mediated lesions to PC12 cells. After initial screening, the most potent neuroprotective compounds 9b and 9c with marginal cytotoxicity were selected for the follow-up studies. Our results demonstrate that their neuroprotective effects are attributed to the up-regulation of a panel of antioxidant genes and corresponding gene products. Further mechanistic studies indicate that Nrf2 is indispensable for the cellular performances of 9b and 9c , arising from the fact that silence of Nrf2 gene drastically nullifies their protective action. Taken together, 9b and 9c discovered in this work merit further development as neuroprotective candidates for the treatment of oxidative stress-mediated pathological conditions.
Designing of multiple-target directed ligands (MTDLs) has emerged as an attractive strategy for Alzheimer's disease (AD). Fusing the benzylpiperidine motif from AChE inhibitor donepezil and the 1,2,4-oxadiazole core from the Nrf2 activator 25 that was previously reported, we designed and synthesized a series of multifunctional anti-AD hybrids. The optimal hybrid 15a exhibited excellent AChE inhibitory ( ee AChE IC 50 = 0.07 ± 0.01 μM; h AChE IC 50 = 0.38 ± 0.04 μM) and significant Nrf2 inductivity. It upregulated the protein and transcription level of Nrf2 and its downstream proteins HO-1, NQO1, and GCLM and promoted Nrf2 translocation from cytoplasm into nuclei. Additionally, 15a exhibited important neuroprotective function in protecting the cells from being damaged by H 2 O 2 and A β 1-42 aggregation and exerted antioxidant stress and anti-inflammatory activities in reducing the production of ROS and pro-inflammatory cytokines. Moreover, 15a effectively shortened the latency time and escape distance to the target, increased the arrival times, and simplified the tracks in Morris water maze test induced by scopolamine and A β 1-42 . At the same time, it significantly reduced the levels of proinflammatory factors in the mice model brains. These effects of 15a in improving cognition and alleviating inflammation were even better than the combination of AChE inhibitor and Nrf2 activator, suggesting a remarkable benefit for AD treatment. 15a could serve as a novel hit compound with Nrf2 inductive activity and AChE inhibitory activity for further research.
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