Sıçan Eritrosit Glukoz 6-Fosfat Dehidrogenaz Enzim İnhibitörleri Olarak Tiyosemikarbazon Temelli Aza-Ylidlerin Sentezi

Year 2019, Volume: 9 Issue: 3, 1503 - 1512, 01.09.2019

Yusuf Temel , Sinan Bayındır

https://doi.org/10.21597/jist.518012

Cited By: 6

Abstract

Glukoz 6-fosfat dehidrogenaz (G6PD) enzimi NADPH, bazı amino asitler, sfingozin, steroid hormonları, kolesterol, yağ asitleri ve riboz 5-fosfat sentezi gibi pek çok biyokimyasal prosesin gerçekleşmesinde çok önemli bir role sahiptir. Bu çalışmada, tiyoasetazon, ambazon ve perklozon gibi birçok ilacın ana iskeletini oluşturan tiyosemikarbazon temelli aza-ylid (TSCAs) türevi 3a-3e moleküllerinin sentezi çevreci bir yaklaşımla gerçekleştirilerek, G6PD enzim aktivitesi üzerine in vitro şartlarda inhibisyon ve aktivasyon etkisi araştırılmıştır. Çalışmalar neticesinde, sentezlenen TSCAs türevleri 3a-3d moleküllerinin G6PD enzim aktivitesini 40.77 μM ile 58.0 μM aralığındaki IC50 değerlerinde inhibe ettiği belirlenmiştir.

Keywords

Tiyosemikarbazon, aza-ylid, sıçan eritrosit, enzim, G6PD

The Synthesis of Thiosemicarbazone-Based Aza-Ylides as Inhibitors of Rat Erythrocyte Glucose 6-Phosphate Dehydrogenase Enzyme

Abstract

Glucose 6-phosphate dehydrogenase (G6PD) enzyme plays an important role in various biochemical processes such as synthesis of cholesterol, fatty acids, sphingosine, steroid hormones, NADPH, some amino acids and ribose 5-phosphate. In this study, thiosemicarbazone-based aza-ylide (TSCAs) derivatives 3a-3e, which form the main framework of many drugs such as thioacetazone, ambazone, and perchlozone, were synthesized with a green approach and in vitro inhibitor or activator effects on G6PD enzyme activity was investigated. As a result of studies, TSCAs derivatives 3a-3d inhibited the G6PD enzyme activity with IC50 in the range of 40.77 μM to 58.0 μM for G6PD.

Keywords

Thiosemicarbazone, aza-ylides, rat eritrosit, enzyme, 6PGD

References

• Aslan, H. E., Demir, Y., Özaslan, M. S., Türkan, F., Beydemir, Ş., Küfrevioğlu, Ö. I., (2018). The behavior of some chalcones on acetylcholinesterase and carbonic anhydrase activity. Drug Chem. Toxicol. 4: 1-7.
• Bayindir S., Toprak M., 2019, A novel pyrene-based selective colorimetric and ratiometric turn-on sensing for copper, Spectrochimica Acta Part A: Molecular and Biomolecular Spectroscopy 213: 6–11.
• Bayindir, S., Ayna, A., Temel, Y., Ciftci, M. 2018a. The synthesis of new oxindoles as analogs of natural product 3, 3'-bis (indolyl) oxindole and in vitro evaluation of the enzyme activity of G6PD and 6PGD. Turkish Journal of Chemistry, 42(2): 332-345.
• Bayindir, S., Temel, Y., Ayna, A., Ciftci, M. 2018b. The synthesis of N‐benzoylindoles as inhibitors of rat erythrocyte glucose‐6‐phosphate dehydrogenase and 6‐phosphogluconate dehydrogenase. Journal of biochemical and molecular toxicology, 32(9): e22193.
• Bayramoğlu Akkoyun, M., Bengü, A. Ş., Temel, Y., Akkoyun, H. T., Ekin, S., Ciftci, M. 2018. The effect of astaxanthin and cadmium on rat erythrocyte G6PD, 6PGD, GR, and TrxR enzymes activities in vivo and on rat erythrocyte 6PGD enzyme activity in vitro. Journal of biochemical and molecular toxicology, 32(8): e22170.
• Beutler, E., 1971. “Red cell metabolism manual of biochemical methods”, London Academic Press: 19-68,
• Beydemir, S., GüLCIN, I., Küfrevioğlu, O. I., Ciftçi, M. 2003. Glucose 6-phosphate dehydrogenase: in vitro and in vivo effects of dantrolene sodium. Polish journal of pharmacology, 55(5): 787-792.
• Bruinenberg, PM., Van Dijken, JP., Scheffers, WA., 1983. “A theoretical analysis of NADPH production and consumption in yeasts”, J. Gen. Microbiol. 129: 953-964,
• Çiftçi, M., Beydemir, Ş., Yılmaz, H., Altıkat, S. (2003). Purification of glucose 6-phosphate dehydrogenase from Buffalo (Bubalus bubalis) erythrocytes and investigation of some kinetic properties. Protein expression and purification, 29(2): 304-310.
• Çiftci, M., Özmen, İ., Büyükokuroğlu, M. E., Pençe, S., Küfrevioğlu, Ö. İ. (2001). Effects of metamizol and magnesium sulfate on enzyme activity of glucose 6-phosphate dehydrogenase from human erythrocyte in vitro and rat erythrocyte in vivo. Clinical biochemistry, 34(4): 297-302.
• Costello C., Karpanen T., Lambert P.A., Mistry P., Parker K.J., Rathbone D.L., Ren, Wheeldon L.J.M., Worthington T., 2008. Thiosemicarbazones active against Clostridium difficile, Bioorg. Med. Chem. Lett 18: 1708-1711.
• Cuperlovic-Culf, M., 2013. “NMR metabolomics in cancer research”, Burlington, Elsevier Science,
• Ebrahimi H.P., Hadi J.S., Alsalim T.A., Ghali T.S., Bolandnazar Z., 2015. A novel series of thiosemicarbazone drugs: from synthesis to structure. Spectrochim. Acta -Part A Mol. Biomol. Spectrosc. 137: 1067-1077.
• Gazieva, G.A.; Kravchenko, A.N., 2012. Thiosemicarbazides in the synthesis of five- and six-membered heterocyclic compounds. Russ. Chem. Rev. 81: 494–523.
• Ghosh P., Mandal S., Das T., Maity A., Gupta P., Purkayastha P., 2012. “Extra stabilization” of a pyrene based molecular couple by C-cyclodextrin in the excited electronic state. Phys. Chem. Chem. Phys. 14: 11500-11507.
• Hassan, A.A.; Shawky, A.M., 2011. Thiosemicarbazides in heterocyclizationJ. Heterocycl. Chem. 48: 495–516.
• Hecker, P. A., Leopold, J. A., Gupte, S. A., Recchia, F. A., Stanley, W. C. 2012. Impact of glucose-6-phosphate dehydrogenase deficiency on the pathophysiology of cardiovascular disease. American Journal of Physiology-Heart and Circulatory Physiology, 304(4): 491-500.
• Jimbow K., Hua C., Gomez P.F., Hirosaki K., Shinoda K., Salopek T.G., Matsusaka H., Jin H.Y., Yamashita T., 2000. Intracellular vesicular trafficking of tyrosinase gene family protein in Eu- and pheomelanosome biogenesis, Pigm. Cell Res. 13: 110-117.
• Kirici, M., Demir, Y., Beydemir, S., Atamanalp, M., 2016. The Effect Of Al+3 And Hg+2 On Glucose 6-Phosphate Dehydrogenase From Capoeta Umbla Kıdney. Appl Ecol Env Res. 14(2): 253-264.
• Kleemann A., Engel J., Kutscher B., Reichert D., 2001. Pharmaceutical Substances: Syntheses, Patents, Applications; Thieme: Stuttgart, pp. 77–78.
• Kuznetsova M.A., Bespalov A.Y., 2014. One-Pot, Three-Component Synthesıs Of [1,3] thiazolo[4,3-B][1,3,4]thiadiazoles: Correct Structure Of The Products, Chemistry of Heterocyclic Compounds, 49: 1458-1463 .
• Lee K.C., Thanigaimalai P., Sharma V.K., Kim M.S., Roh E., Hwang B.Y., Kim Y., Jung S.H., 2010. Structural characteristics of thiosemicarbazones as inhibitors of melanogenesis. Bioorg. Med. Chem. Lett. 20: 6794-6796.
• Lin H., Su H., Li J., Lin H., 2010. An efficient novel acetate anion receptor based on isatin, J. Braz. Chem. Soc. 21: 541-545.
• Lin W.Q., Xie J.X., Wu X.M., Yang L., Wang H.D., 2014. Inhibition of xanthine oxidase activity by Gnaphalium affine extract, Chin. Med J. Peking 29: 225-230.
• Lineweaver, H., Burk, D., 1934. The determination of enzyme dissociation constants. Journal of the American chemical society, 56(3): 658-666.
• Malkina A.G., Nosyreva V.V., Albanov A.I., Afonin A.V., Vashchenko A.V., Amosova S.V., Trofimov B.A., 2017. Regioselective N(2)-H-functionalization of thiosemicarbazones of aromatic and heteroaromatic aldehydes with acrylonitrile, Synthetic Communications, 47:2, 159-168.
• Netalkar P.P., Netalkar S.P., Revankar V.K., 2015. Transition metal complexes of thiosemicarbazone: Synthesis, structures and invitro antimicrobial studies, Polyhedron 100: 215–222.
• Pelosi G., Bisceglie F., Bignami F., Ronzi P., Schiavone P., Re M.C., Casoli C., Pilotti E., 2010. Antiretroviral activity of thiosemicarbazone metal complexes, J. Med. Chem. 53: 8765-8769.
• Pelosi G., Bisceglie F., Bignami F., Ronzi P., Schiavone P., Re M.C., Casoli C., Pilotti E., 2010. Antiretroviral Activity of Thiosemicarbazone Metal Complexes, J. Med. Chem. 53: 8765–8769.
• Şahin M., Koca A., Özdemir N., Dinçer M., Büyükgüngör O., Bal-Demirci T., Ülküseven B., 2010. Synthesis, X-ray crystal structures, thermal and electrochemical properties of thiosemicarbazidatodioxouranium (VI) complexes. Dalton Trans. 39: 10228-10237.
• Sarıgüney A.B., Saf A.Ö., Coskun A., 2014. A newly synthesized thiazole derivative as a fluoride ion chemosensor: naked-eye, spectroscopic, electrochemical and NMR studies, Spectrochim. Acta A, 128: 575-582.
• Smolentsev A.I., Lavrenova L.G., Elokhina V.N., Nakhmanovich A.S., Larina L.I., 2009. Crystal structures of pyridine-4-aldehyde thiosemicarbazone perchlorate and trifluoromethane sulfonate. J. Stuct. Chem. 50: 500-504.
• Temel, Y., Ayna, A., Hamdi Shafeeq, I., Ciftci, M. 2018. In vitro effects of some antibiotics on glucose-6-phosphate dehydrogenase from rat (Rattus norvegicus) erythrocyte. Drug and chemical toxicology, 41: 1-5.
• Temel, Y., Bengü, A. Ş., Akkoyun, H. T., Akkoyun, M., Ciftci, M. 2017. Effect of astaxanthin and aluminum chloride on erythrocyte G6PD and 6PGD enzyme activities in vivo and on erythrocyte G6PD in vitro in rats. Journal of biochemical and molecular toxicology, 31(10): e21954.
• Temel, Y., Kocyigit, U. M. 2017. Purification of glucose‐6‐phosphate dehydrogenase from rat (Rattus norvegicus) erythrocytes and inhibition effects of some metal ions on enzyme activity. Journal of biochemical and molecular toxicology, 31(9): e21927.
• Temel, Y., Taysi, M. Ş. 2018. The Effect of Mercury Chloride and Boric Acid on Rat Erythrocyte Enzymes. Biological trace element research, 186: 1-6.
• Thanigaimalai P., Hoang T.A.L., Lee K.C., Bang S.C., Sharma V.K., Yun C.Y., Roh E., Hwang B.Y., Kim Y., Jung S.H., 2010. Structural requirement(s) of N-phenylthioureas and benzaldehyde thiosemicarbazones as inhibitors of melanogenesis in melanoma B16 cells, Bioorg. Med. Chem. Lett. 20: 2991-2993.
• Thomas, D., Cherest, H., Surdin-Kerjan, Y., 1991. Identification of the structural gene for glucose-6-phosphate dehydrogenase in yeast. Inactivation leads to nutritional requierment for organic sulfur”, EMBO J. 10: 547-553.
• Wang X.M., Yan H., Feng X.L., Chen Y., 2010. 1-Pyrenecarboxaldehyde thiosemicarbazone: A novel fluorescent molecular sensor towards mercury (II) ion, Chinese Chemical Letters 21: 1124–1128.
• Yusuf M., Jain P., 2014. Synthesis and biological significances of 1,3,4-thiadiazolines and related heterocyclic compounds, Arab. J. Chem. 7: 525–552.
• Zhang, C., Zhang, Z., Zhu, Y., Qin, S., 2014. Glucose-6-phosphate dehydrogenase: a biomarker and potential therapeutic target for cancer. Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 14(2): 280-289.
• Zhao H.C., Shi Y.P., Liu Y.M., Li C.W., Xuan L.N., Wang P., Zhang K., Chen B.Q., 2013. Synthesis and antitumor-evaluation of 1,3-selenazole-containing 1,3,4-thiadiazole derivatives, Bioorg. Med. Chem. Lett. 23: 6577-6579.