Minsk, Belarus
Effects of new synthetic sulfur-containing monophenols on erythrocytes and tumor cells were studied. To establish the molecular structure descriptors characterizing the biological activity of the compounds, new synthetic structurally related water-soluble monophenols with varying length of the hydrocarbon chain of the para -alkylthiosulfonate substituent, the amount of tert -butyl ortho -substituents and the "S-S" fragment structure were used: sodium 3-(3'- tert -butyl-4'-hydroxyphenyl)ethyl thiosulfonate (TS-12), sodium 3-(3'- tert -butyl-4'-hydroxyphenyl)propyl sulfonate (S-13), sodium 3-(3'- tert -butyl-4'-hydroxyphenyl)propyl thiosulfonate (TS-13), sodium 3-(3',5'-di- tert -butyl-4'-hydroxyphenyl)propyl thiosulfonate (TS-17). It was shown that the studied monophenols increase the structural stability of human erythrocytes during oxidative hemolysis. However, under the action of the antioxidant C-13, in which the thiosulfonate group in the para -propyl substituent is replaced by the sulfonate group in comparison with other monophenols, the increase in the structural stability of erythrocytes during oxidative hemolysis was several times less in comparison with other antioxidants. It was also found the antitumor activity of several monophenols against human larynx carcinoma cells. It has been established that the key structural descriptor of new sulfur-containing antioxidants, that determine the toxic properties of compounds against tumor cells, is the presence of the thiosulfonate group in the para -propyl compound substituent. The obtained results provide new opportunities for the development of antitumor therapy methods.
antioxidants, reactive oxygen species, erythrocytes, tumor cells, redox regulation
1. Sauer H., Wartenberg M., Hescheler J. Reactive oxygen species as intracellular messengers during cell growth and differentiation. Cellular physiology and biochemistry, 2001, vol. 11, no. 4, pp. 173-186. DOI:https://doi.org/10.1159/000047804.
2. Droge W. Free radicals in the physiological control of cell function. Physiological reviews, 2002, vol. 82, no 1, pp. 47-95. DOI:https://doi.org/10.1152/physrev.00018.2001.
3. Zenkov N.K., Men'schikova E.B., Kandalinceva N.V., Oleynik A.S., Prosenko A.E., Gusachenko O.N., Shklyaeva O.A., Vavilin V.A., Lyahovich V.V. Antioksidantnye i protivovospalitel'nye svoystva novyh vodorastvorimyh serosoderzhaschih fenol'nyh soedineniy. Biohimiya, 2007, t. 72, s. 790-798. [Zenkov N.K., Menshchikova E.B., Kandalintseva N.V., Oleynik A.S., Prosenko A.E., Gusachenko O.N., Shklyaeva O.A., Vavilin V.A., Lyakhovich V.V. Antioxidant and antiinflammatory activity of new water-soluble sulfur-containing phenolic compounds. Biochemistry (Moscow), 2007, vol. 72, no. 6, pp. 644-651. DOI:https://doi.org/10.1134/S0006297907060077.]
4. Yamamoto M., Kensler T.W., Motohashi H. The KEAP1-NRF2 system: a thiol-based sensor-effector apparatus for maintaining redox homeostasis. Physiological reviews, 2018, vol. 98, pr. 1169-1203. DOI:https://doi.org/10.1152/physrev.00023.2017.
5. Cuadrado A., Rojo A.I., Wells G., Hayes J.D., Cousin S.P., Rumsey W.L., Attucks O.C., Franklin S., Levonen A.L., Kensler T.W., Dinkova-Kostova A.T. Therapeutic targeting of the NRF2 and KEAP1 partnership in chronic diseases. Nature Reviews Drug Discovery, 2019, vol. 18, pp. 295-317. DOI:https://doi.org/10.1038/s41573-018-0008-x.
6. Men'schikova E.B., Tkachev V.O., Zenkov N.K., Lemza A.E., Sharkova T.V., Kandalinceva N.V. Protivovospalitel'naya aktivnost' induciruyuschego sistemu antioksidant-responsivnogo elementa (ARE) fenol'nogo antioksidanta TS-13. Byulleten' eksperimental'noy biologii i mediciny, 2013, t. 155, s. 344-348. [Menshchikova E.B., Tkachev V.O., Zenkov N.K., Lemza A.E., Sharkova T.V., Kandalintseva N.V. Anti-Inflammatory Activity of TS-13, ARE-Inducing Phenol Antioxidant. Bulletin of experimental biology and medicine, 2013, vol. 155, no. 3, pp. 366-369. DOI:https://doi.org/10.1007/s10517-013-2155-8.]
7. Men'schikova E.B., Zenkov N.K., Lemza A.E., Tkachev V.O., Kandalinceva N.V. Zaschitnoe deystvie ARE-induciruyuschego fenol'nogo antioksidanta TS-13 pri hronicheskom vospalenii. Byulleten' eksperimental'noy biologii i mediciny, 2013, t. 155, s. 305-309. [Menshchikova E.B., Zenkov N.K., Tkachev V.O., Lemza A.E., Kandalintseva N.V. Protective effect of are-inducing phenol antioxidant TS-13 in chronic inflammation. Bulletin of experimental biology and medicine, 2013, vol. 155, no. 3, pp. 330-334. DOI:https://doi.org/10.1007/s10517-013-2146-9.]
8. Vaysman N.Ya., Men'schikova E.B., Zenkov N.K., Kandalinceva N.V., Golubovskiy M.D. Vliyanie induciruyuschego antioksidant-responsivnyy element fenola na prodolzhitel'nost' zhizni Drosophila melanogaster. Uspehi gerontologii, 2011, t. 24, s. 591-600. [Vaĭsman N., Men'shchikova E.B., Zenkov N.K., Kandalintseva N.V., Golubovskiĭ M.D. Effect of antioxidant responsive element inducing phenol on D. melanogaster life span. Advances in gerontology, 2011, vol. 24, no. 4, pp. 591-600. (In Russ.)]
9. Zucker S.N., Fink E.E., Bagati A., Mannava S., Bianchi-Smiraglia A., Bogner P.N., Wawrzyniak J.A., Foley C., Leonova K.I., Grimm M.J., Moparthy K., Ionov Y., Wang J., Liu S., Sexton S., Kandel E.S., Bakin A.V., Zhang Y., Kaminski N., Segal B.H., Nikiforov M.A. Nrf2 amplifies oxidative stress via induction of Klf9. Molecular cell, 2014, vol. 53, pp. 916-928. DOI:https://doi.org/10.1016/j.molcel.2014.01.033.
10. Martinovich G.G., Martinovich I.V., Zenkov N.K., Men'schikova E.B., Kandalinceva N.V., Cherenkevich S.N. Induktor ekspressii ARE-reguliruemyh genov fenol'nyy antioksidant TS-13 vyzyvaet gibel' opuholevyh kletok cherez mitohondrial'no-oposredovannyy put'. Biofizika, 2015, t. 60, № 1, s. 120-128. [Martinovich G.G., Martinovich I.V., Zenkov N.K., Menshchikova E.B., Kandalintseva N.V., Cherenkevich S.N. Phenolic antioxidant TS-13 regulating ARE-driven genes induces tumor cell death by a mitochondria-dependent pathway. Biophysics, 2015, vol. 60, pp. 94-100. DOI:https://doi.org/10.1134/S0006350915010194.]
11. Martinovich G.G., Martinovich I.V., Vcherashnyaya A.V., Zenkov N.K., Men'schikova E.B., Cherenkevich S.N. Regulyaciya himiorezistentnosti opuholevyh kletok fenol'nymi antioksidantami. Aktual'nye voprosy biologicheskoy fiziki i himii, 2017, t. 2, № 1, s. 411-415. [Martinovich G.G., Martinovich I.V., Vcherashniaya A.V., Zenkov N.K., Menshchikova E.B., Cherenkevich S.N. Regulation of tumor cells chemoresistance by phenolic antioxidants. Russian Journal of Biological Physics and Chemistry, 2017, vol. 2, no. 1, pp. 411-415. (In Russ.)]
12. Martinovich G.G., Martinovich I.V., Vcherashnyaya A.V., Zenkov N.K., Men'schikova E.B., Kandalinceva N.V., Cherenkevich S.N. Mehanizmy redoks-regulyacii himiorezistentnosti opuholevyh kletok fenol'nymi antioksidantami Biofizika, 2017, t. 62, № 6, s. 1142-1152. [Martinovich G.G., Martinovich I.V., Vcherashniaya A.V., Zenkov N.K., Menshchikova E.B., Kandalintseva N.V., Cherenkevich S.N. Mechanisms of redox regulation of chemoresistance in tumor cells by phenolic antioxidants. Biophysics, 2017, vol. 62, no. 6, pp. 942-949. DOI:https://doi.org/10.1134/S000635091706015X.]
13. Bogatyrenko T.N., Kandalinceva N.V., Sashenkova T.E., Mischenko D.V. Serosoderzhaschie fenol'nye antioksidanty v povyshenii protivoopuholevoy effektivnosti ciklofosfana i ego kombinacii s donorom oksida azota. Izvestiya Akademii nauk. Seriya Himicheskaya, 2018, № 4, s. 700-704. [Bogatyrenko T.N., Sashenkova T.E., Mishchenko D.V., Kandalintseva N.V. Sulfur-containing phenolic antioxidants increasing antitumor efficiency of cyclophosphamide and its combination with nitric oxide donor. Russian Chemical Bulletin, 2018, vol. 67, no. 4, pp. 700-704. DOI:https://doi.org/10.1007/s11172-018-2125-4.]
14. Men'schikova E.B., Zenkov N.K., Kozhin P.M., Chechushkov A.V., Kovner A.V., Hrapova M.V., Kandalinceva N.V., Martinovich G.G. Sinteticheskiy fenol'nyy antioksidant TS-13 podavlyaet rost perevivaemoy karcinomy legkih L'yuis i potenciruet onkoliticheskiy effekt doksorubicina. Byulleten' eksperimental'noy biologii i mediciny, 2018, t. 166, № 11, s. 592-597. [Men’shchikova E.B., Zenkov N.K., Kozhin P.M., Chechushkov A.V., Kovner A.V., Khrapova M.V., Kandalintseva N.V., Martinovich G.G. Synthetic phenolic antioxidant TS-13 suppresses the growth of Lewis lung carcinoma and potentiates oncolytic effect of doxorubicin. Bulletin of experimental biology and medicine, 2019, vol. 166, no. 5, pp. 646-650. DOI:https://doi.org/10.1007/s10517-019-04410-6]
15. Gaynutdinov P.I., Kozhin P.M., Chechushkov A.V., Martinovich G.G., Hol'shin S.V., Kandalinceva N.V., Zenkov N.K., Men'schikova E.B. Obratnaya zavisimost' mezhdu antioksidantnoy aktivnost'yu sinteticheskih monofenolov strukturno vzaimosvyazannogo ryada i ih toksichnost'yu v otnoshenii opuholevyh kletok. Sibirskiy nauchnyy medicinskiy zhurnal, 2018, t. 38, № 1, s. 22-31. [Gainutdinov P.I., Kozhin P.M., Chechushkov A.V., Martinovich G.G., Kholshin S.V., Kandalintseva N.V., Zenkov N.K., Menshchikova E.B. Inverse relationship between the antioxidant activity of structurally related synthetic monophenols and their toxicity in tumor cells. Siberian Scientific Medical Journal, 2018, vol. 38, no. 1, pp. 22-31. DOI:https://doi.org/10.15372/SSMJ20180104. (In Russ.)]
16. Zenkov N.K., Kozhin P.M., Vcherashnyaya A.V., Martinovich G.G., Kandalinceva N.V., Men'schikova E.B. Osobennosti redoks-regulyacii v opuholevyh kletkah. Sibirskiy nauchnyy medicinskiy zhurnal, 2019, t. 39, № 9, s. 11-26. [Zenkov N.K., Kozhin P.M., Vcherashnyaya A.V., Martinovich G.G., Kandalintseva N.V., Menshchikova E.B. Futures of redox regulation in tumor cells. Siberian Scientific Medical Journal, 2019, vol. 39, no. 2, pp. 11-26. DOI:https://doi.org/10.15372/SSMJ20190202. (In Russ.)]
