Nitro grubu İçeren Bazı Maddelerin Glutatyon Redüktaz Enzimi Üzerindeki İnhibisyon Etkisinin İncelenmesi

Glutatyon redüktaz (Glutatyon: NADP+ oksidoredüktaz, EC 1.8.1.7; GR) düşük (GSH) veya yüksek molekül ağırlıklı (GSSG) disülfit substratları ile indirgenmiş piridin nükleotidleri (NADPH) arasında elekton transferini katalizler. GR inhibitörleri son zamanlarda anti-sıtma ve kansere karşı faaliyetlerinin keşfedilmesi nedeniyle oldukça popüler hale gelmiştir. Enzimatik aktivite Beutler metodu kullanılarak Spektrofotometre kullanılarak 25°C’de yapıldı. Ölçüm sistemi 100 mM Tris-HCl tamponunda (pH 8.0), 0,5 mM EDTA, 3,3 mM GSSG ve 0,1 mM NADPH içeriyordu. Nitrobenzen (1), 3,5-Dinitrosalisilik asit (2), (2,4-Dinitrofenil) ((4-(prop-1-en-2-yl) sikloheks-1-enil)-metil) sulfan (3), ((7,7-dimetilbisiklo [2.2.1] heptan-1-il)metil)-(2,4-dinitrofenil)sulfan (4) ve ((2-kloro-7,7-dimetilbisiklo [2.2.1] heptan-1-il)metil)-(2,4-dinitrofenil)sulfan (5) maddelerinin GR enzimi üzerindeki in vitro inhibisyon etkisi incelendi. İnhibisyon etkisi gösteren maddeler için % aktivite-[I] grafikleri çizilerek IC50 değerleri bulunmuştur. Bu maddelerin GR için IC50 değerlerinin mikromolar seviyesinde olduğu gözlemlendi.

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  • 1. Schirmer, RH, Krauth-Siegel, RL, Schulz, GE, (1989). Glutathione Reductase, John Wiley and Sons, New York, pp. 553-596.
  • 2. Kocaoglu, E, Talaz, O, Cavdar, H, Senturk, M, Supuran, CT, Ekinci, D. (2018). Determination of the inhibitory effects of N-methylpyrrole derivatives on glutathione reductase enzyme. Journal of Enzyme Inhibition and Medicinal Chemistry. 2018, 34, 51-54.
  • 3. Krauth-Siegel, RL, Bauer, H, Schirmer, RH. (2005). Dithiol proteins as guardians of the intracellular redox milieu in parasites: old and new drug targets in trypanosomes and malaria-causing plasmodia. Angewandte Chemie International Edition, 44, 690-715.
  • 4. Pastore, A, Federici, G, Bertini, E, Piemonte, F. (2003). Analysis of glutathione: implication in redox and detoxification. Clinical Chimica Acta, 333, 19-39.
  • 5. Perricone, C, De Carolis, C, Perricone, R. (2009). Glutathione: a key player in autoimmunity. Autoimmunity Reviews, 8, 697-701.
  • 6. Biot, C, Bauer, H, Schirmer, RH, Davioud-Charvet, E. (2004). 5-Substituted tetrazoles as bioisosteres of carboxylic acids. Bioisosterism and mechanistic studies on glutathione reductase inhibitors as antimalarials. Journal of Medicinal Chemistry, 47, 5972-5983.
  • 7. Grellier, P, Sarlauskas, J, Anusevicius, Z, Maroziene, A, Houee-Levin, C, Schrevel, J, et. al. (2001). Antiplasmodial activity of nitroaromatic and quinoidal compounds: Redox potential vs inhibition of erythrocyte glutathione reductase. Archives of Biochemistry and Biophysics, 393, 199-206.
  • 8. Zhao, Y, Seefeldt, T, Chen, W, Wang, X, Matthees, D, Hub,Y, et. al. (2009). Effects of glutathione reductase inhibition on cellular thiol redox state and related systems. Archives of Biochemistry and Biophysics, 485, 56-62.
  • 9. Ricci, G, De Maria, F, Antonini, G, Turella, P, Bullo, A, Stella, L, et al. (2005). 7-Nitro-2,1,3benzoxadiazole derivatives, a new class of suicide inhibitors for glutathione S-transferases. Mechanism of action of potential anticancer drugs. Journal of Biological Chemistry, 280, 26397-26405.
  • 10. Ascione, A, Cianfriglia, M, Dupuis, ML, Mallano, A, Sau, A, Pellizzari Tregno, F, et al. (2009). The glutathione S-transferase inhibitor 6-(7-nitro-2,1,3benzoxadiazol-4-ylthio)hexanol overcomes the MDR1P-glycoprotein and MRP1-mediated multidrug resistance in acute myeloid leukemia cells. Cancer Chemotherapy and Pharmacology, 64, 419-424.
  • 11. Pasello, M, Michelacci, F, Scionti, I, Hattinger, CM, Zuntini, M, Caccuri, AM, et al. (2008). Overcoming glutathione S-transferase P1-related cisplatin resistance in osteosarcoma. Cancer Research, 68, 6661-6668.
  • 12. Zhuo, R, Kosak, KM, Sankar, S, Wiles, ET, Sun, Y, Zhang, J, et al. (2014). Targeting Glutathione S-transferase M4 in Ewing sarcoma. Frontiers in Pediatrics, 83, 1-9.
  • 13. Tang, H, Yao, X, Yao, C, Zhao, X, Zuo, H, Li, Z. (2017). Anti-colon cancer effect of caffeic acid p-nitro-phenethyl ester in vitro and in vivo and detection of its metabolites. Scientific Reports, 7, 7599, 1-11.
  • 14. Noguchi, K, Uemura, H, Harada, M, Miura, T, Moriyama, M, Fukuoka, H, et al. (2001). Inhibition of PSA flare in prostate cancer patients by administration of flutamide for 2 weeks before initiation of treatment of slow-releasing LH-RH agonist. International Journal of Clinical Oncology, 6, 29-33.
  • 15. Olender, D, Żwawiak, J, Zaprutko, L. (2018). Multidirectional Efficacy of Biologically Active Nitro Compounds Included in Medicines. Pharmaceuticals, 11, 54, 1-29.
  • 16. Beutler E. (1984). Red Cell Metabolism. A manual of biochemical methods. Orlando: Grune and Stratton Inc. p 134.
  • 17. Ozturk Sarikaya, SB, Kaya, AA, Celenk Kaya, E, Senturk, M. (2015). Synthesis and determination of some biological activities of novel 2,4-dinitrophenyl derivatives. Archive der Pharmazie, Chemical Life Science, 348, 214-220
  • 18. Senturk, M, Kufrevioglu, OI, Ciftci, M. (2009). Effects of some analgesic anaesthetic drugs on human erythrocyte glutathione reductase: an in vitro study. Journal of Enzyme Inhibition and Medicinal Chemistry, 24, 420-424.
  • 19. Akkemik, E, Senturk, M, Ozgeris, FB, Taser, P, Ciftci, M. (2011). In vitro effects of some drugs on human erythrocyte glutathione reductase. Turkish Journal of Medicinal Science, 41, 235-241.
  • 20. Ekinci, D., Senturk, M. 2013. Assesment of metal inhibition of antioxidant enzyme glutathione reductase from rainbow trout liver. Journal of Enzyme Inhibition and Medicinal Chemistry. 28 (1) 11-15.
  • 21. Seefeldt, T, Zhao, Y, Chen, W, Raza, AS, Carlson, L, Herman, J, et. al. (2009). Characterization of a Novel Dithiocarbamate Glutathione Reductase Inhibitor and Its Use as a Tool to Modulate Intracellular Glutathione. Journal of Biological Chemistry, 284, 2729-2737.
  • 22. Cakmak, R, Durdagi, S, Ekinci, D, Senturk, M, Topal, G. (2011). Design, synthesis and biological evaluation of novel nitroaromatic compounds as potent glutathione reductase inhibitors. Bioorganic & Medicinal Chemistry Letters, 21, 5398-5402.
  • 23. Turella, P, Filomeni, G, Dupuis, ML, Ciriolo, MR, Molinari, A, De Maria, F, et al. (2006). A strong glutathione S-transferase inhibitor overcomes the P-glycoprotein-mediated resistance in tumor cells. 6 (7-Nitro-2,1,3-benzoxadiazol-4-ylthio) hexanol (NBDHEX) triggers a caspase-dependent apoptosis in MDR1-expressing leukemia cells. Journal of Biological Chemitry, 281, 23725-23732.
  • 24. Ascione, A, Cianfriglia, M, Dupuis, ML, Mallano, A, Sau, A, Pellizzari Tregno, F, et al. (2009). The glutathione S-transferase inhibitor 6-(7-nitro-2,1,3-benzoxadiazol-4-ylthio)hexanol overcomes the MDR1-P-glycoprotein and MRP1-mediated multidrug resistance in acute myeloid leukemia cells. Cancer Chemotherapy and Pharmacology, 64, 419-425.
  • 25. Couto, N, Wood, J, Barber, J. (2016). The role of glutathione reductase and related enzymes on cellular redox homoeostasis network. Free Radical Biological Medicine. 95, 27-42.
  • 26. Benhar, M, Shytaj, IL, Stamler, JS, Savarino, A. (2016). Dual targeting of the thioredoxin and glutathione systems in cancer and HIV. Journal of Clinical Investigate, 126,1630-1639.