Nrf2 transcription factor plays a key role in maintaining cellular redox balance under stress and is a perspective target for oxidative stress-associated diseases. Under normal conditions, Nrf2 transcriptional activity is low due to its rapid ubiquitination and degradation in the 26S proteasome, as well as through various modifications of amino acid residues of this transcription factor that regulate its transport to the nucleus and binding to DNA. Continuous activation of Nrf2 is possible due to autophagy and epigenetic regulation that may underlie the increased resistance of tumor cells to radiotherapy and chemotherapy. This review deals with the mechanisms of regulation of Nrf2 transcriptional activity and its main elements, and pharmacological approaches to activation of the Keap1/Nrf2/ARE system.

We synthesized a series of structurally related water-soluble alkyl phenols - sodium 4-hydroxyphenyl propyl sulfonates and thiosulfonates with different number of tert-butyl groups at the ortho-position. In experimental systems of transient metal-induced ethyl oleate and low-density lipoprotein oxidation the antioxidant activity of the compounds increased when the tert-butyl group number at the ortho-position increased and when the sulfonate group was replaced with thiosulfonate. Compounds containing thiosulfonate group in para-propyl substituent also more effectively inhibited reactive oxygen metabolites generated in xanthine-xanthine oxidase system and during morpholinosydnonimine decomposition compared to sulfonate-containing analogs. Phenols with one tert-butyl group at the ortho-position have been shown to exhibit the highest antiinflammatory activity in the model of carrageenan-induced rat paw inflammation, as well as with regard to the expression of the glutathione S-transferase P1-1 gene in HepG2 human hepatoma cell line. Thus, it can be reasonably speculated that the antiinflammatory activity of sulfur-containing phenolic antioxidants in vivo is mediated by their effect on redox-sensitive transcription factors.

Many plant phenols (stilbenes, curcumins, catechins, flavonoids, etc.) are effective antioxidants and protect cells during oxidative stress. Extensive clinical studies on the potential of phenolic compounds for treatment of cardiovascular, neurodegenerative, oncological, and inflammatory diseases are now being conducted. In addition to direct antioxidant effect, plant phenols may provide a protective effect via activation of the Keap1/Nrf2/ARE redox-sensitive signaling system and regulation of autophagy. In this review, mechanisms of effects of the most common plant phenols on autophagy are presented.

Sodium S [3 (hydroxyaryl)propyl] thiosulfates and [3 (hydroxyaryl)propane] 1 sulfonates with various spatial hindrance of their phenolic ОН groups were synthesized from dialkylphenols via a number of intermediate products. On a model reaction of oxidation of methyl oleate in aqueous sodium dodecyl sulfate, the rate constants of the interaction of the synthesized com pounds with lipoperoxide radicals were determined.A creation of hydrophilic "hybrid" compounds with several antioxidant active centers in the molecule, which can inhibit a peroxidation of lipids in different ways, is one of the priorities in a search of new antioxidants to be used in biology and medicine. Derivatives of spatially hindered phenols, in which para substituent contains alkylammonium, 1-4 isothiuronium, 3,4 and thiosulfate 4,5 groups, are among such compounds. In particular, it was earlier shown that sodium S [3 (3,5 di tert butyl 4 hydroxyphenyl)propyl] thiosulfate (1а) is characterized by a high antioxidant activity due to a concerted action of the phenol and thiosulfate groups 5 and shows hepato protecting, 4 cardioprotecting, 6 and immunomodulating 7 activities.The present work is aimed on the synthesis of struc tural analogs of compound 1а, viz., thiosulfates 1 and sulfonates 2, and on the comparative study of their anti radical activity.Compounds 1 and 2 were obtained from 2,6 dialkyl phenols via the intermediate transformation of the latter to (3 hydroxypropyl)phenols and halogen derivatives 3a-i and 4a-i, respectively.According to the known method, 8 alkylation of 2,6 di tert butylphenol with allyl alcohol in the presence of NaOH gave alcohol 3а, which upon treatment with PBr 3 was converted to bromide 4а, 9 upon treatment with HBr, to bromide 4d, and by thermolysis, to alcohol 3g. 10 Treat ment of the latter with PBr 3 led to bromide 4g (Scheme 1).In contrast to 2,6 di tert butylphenol, its less hindered analogs react with allyl alcohol not that straightforward: a remarkable amount of by products is formed, resulting * Dedicated to the memory of Academician N. N. Vorozhtsov on the 100th anniversary of his birth. R 1 = R 2 = Bu t (а); R 1 = R 2 = cyclo C 6 H 11 (b); R 1 = R 2 = Me (c); R 1 = R 2 = H (d); R 1 = Me, R 2 = Bu t (e); R 1 = Me, R 2 = cyclo C 6 H 11 (f); R 1 = H, R 2 = Bu t (g); R 1 = Н, R 2 = cyclo C 6 H 11 (h)

Three new sulfur-containing derivatives of 2,6-dimethylphenol were synthesized. Their antioxidative activity, mutagenicity, and genotoxicity were examined by bacterial tests and by calculating the dominant lethal mutations in murine embryonic cells. It was shown that all the compounds synthesized have a marked antioxidative effect and no genotoxic or mutagenic properties. One of the antioxidants, 4-(3-dodecylthiopropyl)-2,6-dimethylphenol, increases the survival of cells of both the wild-type Escherichia coli strain and bacterial strains defective in the genes of repair enzymes and has a more distinct antioxidative effect than the classic antioxidants alpha-tocopherol and trolox, increasing the survival of cells devoid of repair enzymes.