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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Research Article

Zidovudine Glycosylation by Filamentous Fungi Leads to a Better Redox Stability and Improved Cytotoxicity in B16F10 Murine Melanoma Cells

Author(s): Evilanna L. Arruda*, Kamila B. Japiassu, Paula L. de Melo Souza, Kelly C.F. Araújo, Douglas V. Thomaz, Alane P. Cortez, Luane F. Garcia, Marize C. Valadares, Eric de Souza Gil and Valéria de Oliveira

Volume 20 , Issue 14 , 2020

Page: [1688 - 1694] Pages: 7

DOI: 10.2174/1871520620666200424112504

Price: $65


Background: The strategic development of therapeutic agents, capable of being targeted at their active sites, has been a major goal in treatment of cancer. The delivery of drugs for tumors has as its main challenge the development of safe and effective drugs, since the goal of chemotherapy is to eliminate the tumor completely without affecting healthy cells. The aim of present study was to investigate the antioxidant, anticancer activities of zidovudine and its α-O-glycosylated derivative obtained by biosynthesis of a filamentous fungi, Cunninghamela echinulata.

Methods: An evaluation of the cytotoxic potential of zidovudine and its α-O-glycosylated was performed in fibroblasts and melanoma cells by the tetrazolium reduction method (MTT) and the antioxidant activity of this derivative was observed.

Results: The antioxidant activity of zidovudine demonstrated an electrochemical oxidation potential of 0.91V, while the α-O-glycosylated derivative did not exhibit any antioxidant activity. The zidovudine exhibited low cytotoxicity for melanoma and fibroblast cells, while the α-O-glycosylated derivative presented better cytotoxicity on melanoma cells at a concentration of 10mg. mL-1.

Conclusion: This study demonstrates the specific cytotoxicity of the glycoconjugate and suggests that glycosylation by biosynthesis can be a useful strategy for obtaining new anticancer compounds.

Keywords: Glycoconjugate, zidovudine, antioxidant, anticancer, biotransformation, Cunninghamella echinulata.

Graphical Abstract
Chen, P.; Liu, Y.; Sun, Y.; Chen, C.; Qi, Y.; Zhang, Y. AZT and emodin exhibit synergistic growth-inhibitory effects on K562/ADM cells by inducing S phase cell cycle arrest and suppressing MDR1 mRNA/p-gp protein expression. Pharm. Biol., 2013, 51(12), 1586-1591.
[] [PMID: 24004004]
Humer, J.; Ferko, B.; Waltenberger, A.; Rapberger, R.; Pehamberger, H.; Muster, T. Azidothymidine inhibits melanoma cell growth in vitro and in vivo. Melanoma Res., 2008, 18(5), 314-321.
[] [PMID: 18781129]
Wagner, C.R.; Ballato, G.; Akanni, A.O.; McIntee, E.J.; Larson, R.S.; Chang, S.; Abul-Hajj, Y.J. Potent growth inhibitory activity of zidovudine on cultured human breast cancer cells and rat mammary tumors. Cancer Res., 1997, 57(12), 2341-2345.
[PMID: 9192804]
Wu, D.; Ji, S.; Wu, Y.; Ju, Y.; Zhao, Y. Design, synthesis, and antitumor activity of bile acid-polyamine-nucleoside conjugates. Bioorg. Med. Chem. Lett., 2007, 17(11), 2983-2986.
[] [PMID: 17416522]
Galmarini, C.M.; Mackey, J.R.; Dumontet, C. Nucleoside analogues and nucleobases in cancer treatment. Lancet Oncol., 2002, 3(7), 415-424.
[]] [PMID: 12142171]
Jordheim, L.P.; Durantel, D.; Zoulim, F.; Dumontet, C. Advances in the development of nucleoside and nucleotide analogues for cancer and viral diseases. Nat. Rev. Drug Discov., 2013, 12(6), 447-464.
[]] [PMID: 23722347]
Wang, K.; Wu, L.; Qin, Z.; Yan, X.; Li, X.; Chen, H.; Zhang, P.; Zhang, J. Synthesis and antitumor activity of novel ribonucleosides with C-5 OH replaced by a diaminopyrimidinyl group. Bioorg. Med. Chem. Lett., 2011, 21(3), 916-919.
Amatore, C.; Arbault, S.; Jaouen, G.; Koh, A.C.; Leong, W.K.; Top, S.; Valleron, M.A.; Woo, C.H. Pro-oxidant properties of AZT and other thymidine analogues in macrophages: Implication of the azido moiety in oxidative stress. ChemMedChem, 2010, 5(2), 296-301.
[]] [PMID: 20063338]
Azmi, A.S.; Sarkar, F.H.; Hadi, S.M. Pro-oxidant activity of dietary chemopreventive agents: An under-appreciated anti-cancer property. F1000 Res., 2013, 2(135), 135.
[] [PMID: 24358870]
Galore-Haskel, G.; Nemlich, Y.; Greenberg, E.; Ashkenazi, S.; Hakim, M.; Itzhaki, O.; Shoshani, N.; Shapira-Fromer, R.; Ben-Ami, E.; Ofek, E.; Anafi, L.; Besser, M.J.; Schachter, J.; Markel, G. A novel immune resistance mechanism of melanoma cells controlled by the ADAR1 enzyme. Oncotarget, 2015, 6(30), 28999-29015.
[] [PMID: 26338962]
Currie, C.J.; Poole, C.D.; Gale, E.A. The influence of glucose-lowering therapies on cancer risk in type 2 diabetes. Diabetologia, 2009, 52(9), 1766-1777.
[] [PMID: 19572116]
Agarwal, A.; Saraf, S.; Asthana, A.; Gupta, U.; Gajbhiye, V.; Jain, N.K. Ligand based dendritic systems for tumor targeting. Int. J. Pharm., 2008, 350(1-2), 3-13.
[] [PMID: 18162345]
Häuselmann, I.; Borsig, L. Altered tumor-cell glycosylation promotes metastasis. Front. Oncol., 2014, 4(28), 28.
[PMID: 24592356]
Monsigny, M.; Roche, A.C.; Midoux, P.; Mayer, R. Drug and gene targeting with (glyco)-proteins and other glycoconjugates glycoconjugates as carriers for specific delivery of therapeutic drugs and genes. Adv. Drug Deliv. Rev., 1994, 14(1), 1-24.
Kolasińska, E.; Przybyło, M.; Janik, M.; Lityńska, A. Towards understanding the role of sialylation in melanoma progression. Acta Biochim. Pol., 2016, 63(3), 533-541.
[] [PMID: 27474400]
Jain, K.; Kesharwani, P.; Gupta, U.; Jain, N.K. A review of glycosylated carriers for drug delivery. Biomaterials, 2012, 33(16), 4166-4186.
[] [PMID: 22398205]
Seeberger, P.H.; Finney, N.; Rabuka, D.; Bertozzi, C.R. Chemical and enzymatic synthesis of glycans and glycoconjugates. In: Essentials of Glycobiology; Varki, A.; Cummings, R.D.; Esko, J.D., Eds.; Cold Spring Harbor, (NY): Nova York, 2009.
Demchenko, A.V. General Aspects of the Glycosidic Bond Formation Handbook of Chemical Glycosylation. In: Handbook of Chemical Glycosylation: Advances in Stereoselectivity and Therapeutic Relevance; Demchenko, A.V., Ed.; WILEY-YCH, 2008; Vol. 1, pp. 1-27.
Arruda, E.L.; Nunes, S.E.; Souza, P.L.M.; Japiassú, K.B.; Carvalho, T.C.; Vaz, B.G.; Lião, L.M.; de Oliveira, V. A single-step O-glycosylation of azidothymidine in bioreactor catalysed by filamentous fungi. Tetrahedron Lett., 2016, 57(39), 4392-4394.
Boltje, T.J.; Kim, J.H.; Park, J.; Boons, G.J. Chiral-auxiliary-mediated 1,2-cis-glycosylations for the solid-supported synthesis of a biologically important branched alpha-glucan. Nat. Chem., 2010, 2(7), 552-557.
[] [PMID: 20571573]
Gimadieva, A.R.; Khazimullina, Y.Z.; Belaya, E.A.; Zimin, Y.S.; Abdrakhmanov, I.B.; Mustafin, A.G. Express evaluation of antioxidant activity of uracil derivatives. Biomed. Khim., 2015, 61(6), 765-769.
[] [PMID: 26716750]
López-Galilea, I.; Andueza, S.; Leonardo, I.; Paz de Peña, M.; Cid, C. Influence of torrefacto roast on antioxidant and pro-oxidant activity of coffee. Food Chem., 2006, 94(1), 75-80.
Yamauchi, R.; Goto, Y.; Kato, K.; Ueno, Y. Prooxidant effect of dihydroxyacetone and reducing sugars on the autoxidation of methyl linoleate in emulsions. J. Agr. Biol. Chem., 1984, 48(4), 843-848.
Couée, I.; Sulmon, C.; Gouesbet, G.; El Amrani, A. Involvement of soluble sugars in reactive oxygen species balance and responses to oxidative stress in plants. J. Exp. Bot., 2006, 57(3), 449-459.
[] [PMID: 16397003]
Aschacher, T.; Sampl, S.; Käser, L.; Bernhard, D.; Spittler, A.; Holzmann, K.; Bergmann, M. The combined use of known antiviral reverse transcriptase inhibitors AZT and DDI induce anticancer effects at low concentrations. Neoplasia, 2012, 14(1), 44-53.
[] [PMID: 22355273]
Garg, M.; Jain, N.K. Reduced hematopoietic toxicity, enhanced cellular uptake and altered pharmacokinetics of azidothymidine loaded galactosylated liposomes. J. Drug Target., 2006, 14(1), 1-11.
[] [PMID: 16603446]
Arthur, G.; Schweizer, F.; Ogunsina, M. Synthetic Glycosylated Ether Glycerolipids as Anticancer Agents. In: Carbohydrates in Drug Design and Discovery; The Royal Society of Chemistry; Barbero, J.J.; Canada, F.J.; Sonsoles, M.S., Eds.; RSC Publishing, 2015, 43, pp. 151-179..

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