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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Identification of 3-Bromo-1-Ethyl-1H-Indole as a Potent Anticancer Agent with Promising Inhibitory Effects on GST Isozymes

Author(s): Can Yılmaz, Sevki Arslan*, Dogukan Mutlu, Metin Konus, Abdussamet Kayhan, Aslıhan Kurt-Kızıldoğan, Çiğdem Otur, Omruye Ozok and Arif Kivrak*

Volume 21, Issue 10, 2021

Published on: 18 September, 2020

Page: [1292 - 1300] Pages: 9

DOI: 10.2174/1871520620666200918111940

Price: $65

Abstract

Background: Indole-based heterocyclic compounds play important roles in pharmaceutical chemistry due to their unexpected biological and pharmacological properties.

Objective: Herein, we describe novel biological properties (antioxidant, antimicrobial and anti-cancer) of 3- bromo-1-ethyl-1H-indole (BEI) structure.

Methods: BEI was synthesized from 1-Methyl-2-phenylindole and N-bromosuccinimide and was characterized by using 1H and 13C NMR. Cytotoxicity was determined by MTT assay. Apoptosis analysis of BEI was determined by Arthur™ image-based Cytometer. Different methods were applied to assess the antioxidant activity of BEI. Molecular docking studies were conducted to determine the interactions of bonding between GST isozymes and BEI.

Results: According to the antioxidant and antimicrobial activity assays, BEI compound showed reduced total antioxidant activity compared to the Trolox standard, whereas it showed moderate antimicrobial activity against Aspergillus niger and Phytophora eryhtrospora. Notably, the BEI compound demonstrated substantial selective cytotoxicity for the first time towards cancer cell lines, and there existed a significant decrease in the percentage of live cells treated with BEI, in comparison to the control ones. Interestingly, BEI exhibited a promising glutathione S-transferase isozymes inhibition.

Conclusion: The results of this study suggest that BEI seems to be a promising molecule to be used in the design of new anti-cancer agents that provide superiority to present commercial anti-cancer drugs.

Keywords: Indole, biological activities, cytotoxicity, antioxidant activity, antimicrobial activity, anti-cancer.

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[1]
Le Goff, G.; Ouazzani, J. Natural hydrazine-containing compounds: Biosynthesis, isolation, biological activities and synthesis. Bioorg. Med. Chem., 2014, 22(23), 6529-6544.
[http://dx.doi.org/10.1016/j.bmc.2014.10.011] [PMID: 25456382]
[2]
Gurkok, G.; Altanlar, N.; Suzen, S. Investigation of antimicrobial activities of indole-3-aldehyde hydrazide/hydrazone derivatives. Chemotherapy, 2009, 55(1), 15-19.
[http://dx.doi.org/10.1159/000166999] [PMID: 18974644]
[3]
Inman, M.; Moody, C.J. Indole synthesis-something old, something new. Chem. Sci. , 2013, 1, 29-41.
[4]
Shi, Z.; Nie, K.; Liu, C.; Zhang, M-Z.; Zhang, W. Biological activities of 3-(5-oxazolyl)indole natural products and advances on synthesis of its derivatives. Youji Huaxue, 2020, 40, 327.
[http://dx.doi.org/10.6023/cjoc201907047]
[5]
Karaaslan, C.; Kadri, H.; Coban, T.; Suzen, S.; Westwell, A.D. Synthesis and antioxidant properties of substituted 2-phenyl-1H-indoles. Bioorg. Med. Chem. Lett., 2013, 23(9), 2671-2674.
[http://dx.doi.org/10.1016/j.bmcl.2013.02.090] [PMID: 23540647]
[6]
Ali, N.A.; Dar, B.A.; Pradhan, V.; Farooqui, M. Chemistry and biology of indoles and indazoles: A mini-review. Mini Rev. Med. Chem., 2013, 13(12), 1792-1800.
[http://dx.doi.org/10.2174/1389557511313120009] [PMID: 22625410]
[7]
Süzen, S. Antioxidant activities of synthetic indole derivatives and possible activity mechanisms.In: Bioactive Heterocycles V; Springer: Heidelberg, Berlin, 2007, pp. 145-178.
[http://dx.doi.org/10.1007/7081_2007_074]
[8]
Rani, P.; Srivastava, V.K.; Kumar, A. Synthesis and antiinflammatory activity of heterocyclic indole derivatives. Eur. J. Med. Chem., 2004, 39(5), 449-452.
[http://dx.doi.org/10.1016/j.ejmech.2003.11.002] [PMID: 15110970]
[9]
Radwan, M.A.A.; Ragab, E.A.; Sabry, N.M.; El-Shenawy, S.M. Synthesis and biological evaluation of new 3-substituted indole derivatives as potential anti-inflammatory and analgesic agents. Bioorg. Med. Chem., 2007, 15(11), 3832-3841.
[http://dx.doi.org/10.1016/j.bmc.2007.03.024] [PMID: 17395469]
[10]
Unangst, P.C.; Connor, D.T.; Stabler, S.R.; Weikert, R.J.; Carethers, M.E.; Kennedy, J.A.; Thueson, D.O.; Chestnut, J.C.; Adolphson, R.L.; Conroy, M.C. Novel indolecarboxamidotetrazoles as potential antiallergy agents. J. Med. Chem., 1989, 32(6), 1360-1366.
[http://dx.doi.org/10.1021/jm00126a036] [PMID: 2470904]
[11]
Giampieri, M.; Balbi, A.; Mazzei, M.; La Colla, P.; Ibba, C.; Loddo, R. Antiviral activity of indole derivatives. Antiviral Res., 2009, 83(2), 179-185.
[http://dx.doi.org/10.1016/j.antiviral.2009.05.001] [PMID: 19445965]
[12]
Andreani, A.; Burnelli, S.; Granaiola, M.; Leoni, A.; Locatelli, A.; Morigi, R.; Rambaldi, M.; Varoli, L.; Landi, L.; Prata, C.; Berridge, M.V.; Grasso, C.; Fiebig, H.H.; Kelter, G.; Burger, A.M.; Kunkel, M.W. Antitumor activity of bis-indole derivatives. J. Med. Chem., 2008, 51(15), 4563-4570.
[http://dx.doi.org/10.1021/jm800194k] [PMID: 18598018]
[13]
Zhang, F.; Zhao, Y.; Sun, L.; Ding, L.; Gu, Y.; Gong, P. Synthesis and anti-tumor activity of 2-amino-3-cyano-6-(1H-indol-3-yl)-4-phenylpyridine derivatives in vitro. Eur. J. Med. Chem., 2011, 46(7), 3149-3157.
[http://dx.doi.org/10.1016/j.ejmech.2011.03.055] [PMID: 21514012]
[14]
Zhu, W.; Bao, X.; Ren, H.; Da, Y.; Wu, D.; Li, F.; Yan, Y.; Wang, L.; Chen, Z. N-Phenyl indole derivatives as AT1 antagonists with anti-hypertension activities: Design, synthesis and biological evaluation. Eur. J. Med. Chem., 2016, 115, 161-178.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.021] [PMID: 27017546]
[15]
Biradar, J.S.; Sasidhar, B.S.; Parveen, R. Synthesis, antioxidant and DNA cleavage activities of novel indole derivatives. Eur. J. Med. Chem., 2010, 45(9), 4074-4078.
[http://dx.doi.org/10.1016/j.ejmech.2010.05.067] [PMID: 20594623]
[16]
Demurtas, M.; Baldisserotto, A.; Lampronti, I.; Moi, D.; Balboni, G.; Pacifico, S.; Vertuani, S.; Manfredini, S.; Onnis, V. Indole derivatives as multifunctional drugs: Synthesis and evaluation of antioxidant, photoprotective and antiproliferative activity of indole hydrazones. Bioorg. Chem., 2019, 85, 568-576.
[http://dx.doi.org/10.1016/j.bioorg.2019.02.007] [PMID: 30825715]
[17]
Sondhi, S.M.; Dinodia, M.; Kumar, A. Synthesis, anti-inflammatory and analgesic activity evaluation of some amidine and hydrazone derivatives. Bioorg. Med. Chem., 2006, 14(13), 4657-4663.
[http://dx.doi.org/10.1016/j.bmc.2006.02.014] [PMID: 16504522]
[18]
Shirinzadeh, H.; Altanlar, N.; Yucel, N.; Ozden, S.; Suzen, S. Antimicrobial evaluation of indole-containing hydrazone derivatives. Z. Natforsch. C J. Biosci., 2011, 66(7-8), 340-344.
[http://dx.doi.org/10.1515/znc-2011-7-804] [PMID: 21950157]
[19]
Kaushik, N.K.; Kaushik, N.; Attri, P.; Kumar, N.; Kim, C.H.; Verma, A.K.; Choi, E.H. Biomedical importance of indoles. Molecules, 2013, 18(6), 6620-6662.
[http://dx.doi.org/10.3390/molecules18066620] [PMID: 23743888]
[20]
Zhao, X.; Li, Q.; Xu, J.; Wang, D.; Zhang-Negrerie, D.; Du, Y. Cascade synthesis of benzothieno[3,2- b]indoles under oxidative conditions mediated by CuBr and tert-butyl hydroperoxide. Org. Lett., 2018, 20(18), 5933-5937.
[http://dx.doi.org/10.1021/acs.orglett.8b02614] [PMID: 30211558]
[21]
Worlikar, S.A.; Neuenswander, B.; Lushington, G.H.; Larock, R.C. Highly substituted indole library synthesis by palladium-catalyzed coupling reactions in solution and on a solid support. J. Comb. Chem., 2009, 11(5), 875-879.
[http://dx.doi.org/10.1021/cc900057n] [PMID: 19746991]
[22]
Vo, Q.V.; Van Bay, M.; Nam, P.C.; Mechler, A. Hydroxyl radical scavenging of indole-3-carbinol: A mechanistic and kinetic study. ACS Omega, 2019, 4(21), 19375-19381.
[http://dx.doi.org/10.1021/acsomega.9b02782] [PMID: 31763562]
[23]
Yeh, H.T.; Tsai, Y.S.; Chen, M.S.; Li, Y.Z.; Lin, W.C.; Lee, Y.R.; Tseng, Y.S.; Sheu, S.M. Flavopereirine induces cell cycle arrest and apoptosis via the AKT/p38 MAPK/ERK1/2 signaling pathway in human breast cancer cells. Eur. J. Pharmacol., 2019, 863, 172658.
[http://dx.doi.org/10.1016/j.ejphar.2019.172658] [PMID: 31518562]
[24]
Rashid, H.U.; Xu, Y.; Muhammad, Y.; Wang, L.; Jiang, J. Research advances on anticancer activities of matrine and its derivatives: An updated overview. Eur. J. Med. Chem., 2019, 161, 205-238.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.037] [PMID: 30359819]
[25]
Liu, W.; Li, Q.; Hu, J.; Wang, H.; Xu, F.; Bian, Q. Application of natural products derivatization method in the design of targeted anticancer agents from 2000 to 2018. Bioorg. Med. Chem., 2019, 27(23), 115150.
[26]
Zora, M.; Demirci, D.; Kivrak, A.; Kelgokmen, Y. One-pot synthesis of 4-(phenylselanyl)-. Substituted Pyrazoles. Tetrahedron Lett., 2016, 57(9), 993-997.
[http://dx.doi.org/10.1016/j.tetlet.2016.01.071]
[27]
Konus, M.; Aydemir, S.; Yilmaz, C.; Kivrak, A.; Kizildogan, A.K.; Arpacı, P.U. Synthesis and evaluation of antioxidant, antimicrobial and anticancer properties of 2-(Prop-2-Yn-1-Yloxy)benzaldehyde derivatives. Lett. Org. Chem., 2019, 16(5), 415-423.
[http://dx.doi.org/10.2174/1570178616666181116100232]
[28]
Algso, M.A.S.; Kivrak, A. New strategy for the synthesis of 3-ethynyl-2-(thiophen-2-Yl)benzo[b]thiophene derivatives. Chem. Pap., 2019, 73(4), 977-985.
[http://dx.doi.org/10.1007/s11696-018-0640-2]
[29]
Wolfe, K.L.; Liu, R.H. Cellular Antioxidant Activity (CAA) assay for assessing antioxidants, foods, and dietary supplements. J. Agric. Food Chem., 2007, 55(22), 8896-8907.
[http://dx.doi.org/10.1021/jf0715166] [PMID: 17902627]
[30]
Amorati, R.; Valgimigli, L. Advantages and limitations of common testing methods for antioxidants. Free Radical Res., 2015, 49(5), 633-649.
[http://dx.doi.org/10.3109/10715762.2014.996146]
[31]
Honzel, D.; Carter, S.G.; Redman, K.A.; Schauss, A.G.; Endres, J.R.; Jensen, G.S. Comparison of chemical and cell-based antioxidant methods for evaluation of foods and natural products: Generating multifaceted data by parallel testing using erythrocytes and polymorphonuclear cells. J. Agric. Food Chem., 2008, 56(18), 8319-8325.
[http://dx.doi.org/10.1021/jf800401d] [PMID: 18717566]
[32]
Townsend, D.M.; Tew, K.D. The role of glutathione-S-transferase in anti-cancer drug resistance. Oncogene, 2003, 22(47), 7369-7375.
[http://dx.doi.org/10.1038/sj.onc.1206940] [PMID: 14576844]
[33]
Lu, Y.; Gao, X. Multiple mechanisms responsible for differential susceptibilities of Sitobion avenae (Fabricius) and Rhopalosiphum padi (Linnaeus) to pirimicarb. Bull. Entomol. Res., 2009, 99(6), 611-617.
[http://dx.doi.org/10.1017/S0007485309006725] [PMID: 19413913]
[34]
Baglai, I.; Maraval, V.; Bijani, C.; Saffon-Merceron, N.; Voitenko, Z.; Volovenko, Y.M.; Chauvin, R. Enhanced π-frustration in carbo-benzenic chromophores. Chem. Commun. (Camb.) , 2013, 49(75), 8374-8376.
[http://dx.doi.org/10.1039/c3cc43204a] [PMID: 23936897]
[35]
Ye, Z.; Song, H.; Higgins, J.P.T.; Pharoah, P.; Danesh, J. Five glutathione s-transferase gene variants in 23,452 cases of lung cancer and 30,397 controls: Meta-analysis of 130 studies. PLoS Med., 2006, 3(4), e91.
[http://dx.doi.org/10.1371/journal.pmed.0030091] [PMID: 16509765]
[36]
Konishi, T.; Kato, K.; Araki, T.; Shiraki, K.; Takagi, M.; Tamaru, Y. A new class of glutathione S-transferase from the hepatopancreas of the red sea bream Pagrus major. Biochem. J., 2005, 388(Pt 1), 299-307.
[http://dx.doi.org/10.1042/BJ20041578] [PMID: 15610066]
[37]
Brand-Williams, W.; Cuvelier, M.E.; Berset, C. Use of a free radical method to evaluate antioxidant activity. LWT - Food Sci, . Technol.,. 1995, 28(1), 25-30.
[http://dx.doi.org/10.1016/S0023-6438(95)80008-5]
[38]
MacDonald-Wicks, L.K.; Wood, L.G.; Garg, M.L. Methodology for the determination of biological antioxidant capacity in vitro: A review. J. Sci. Food Agric., 2006, 86(13), 2046-2056.
[39]
Feng, J.Y.; Liu, Z.Q. Phenolic and enolic hydroxyl groups in curcumin: Which plays the major role in scavenging radicals? J. Agric. Food Chem., 2009, 57(22), 11041-11046.
[http://dx.doi.org/10.1021/jf902244g] [PMID: 19736944]
[40]
Karadag, A.; Ozcelik, B.; Saner, S. Review of methods to determine antioxidant capacities. Food Anal. Methods, 2009, 2(1), 41-60.
[http://dx.doi.org/10.1007/s12161-008-9067-7]
[41]
Benzie, I.F.F.; Strain, J.J. The Ferric Reducing Ability of Plasma (FRAP) as a measure of “antioxidant power”: The FRAP assay. Anal. Biochem., 1996, 239(1), 70-76.
[http://dx.doi.org/10.1006/abio.1996.0292] [PMID: 8660627]
[42]
Cao, S.; Chen, X.; Chen, L.; Chen, J. α(N)-heterocyclic thiosemicarbazones: Iron chelators that are promising for revival of gallium in cancer chemotherapy. Anticancer. Agents Med. Chem., 2016, 16(8), 973-991.
[http://dx.doi.org/10.2174/1871520616666160310142012] [PMID: 26961317]
[43]
Doens, D.; Valdés-Tresanco, M.E.; Vasquez, V.; Carreira, M.B.; De La Guardia, Y.; Stephens, D.E.; Nguyen, V.D.; Nguyen, V.T.; Gu, J.; Hegde, M.L.; Larionov, O.V.; Valiente, P.A.; Lleonart, R.; Fernández, P.L. Hexahydropyrrolo[2,3-b]indole compounds as potential therapeutics for Alzheimer’s disease. ACS Chem. Neurosci., 2019, 10(10), 4250-4263.
[http://dx.doi.org/10.1021/acschemneuro.9b00297] [PMID: 31545596]
[44]
Lim, H.R.; Kim, S.Y.; Jeon, E.H.; Kim, Y.L.; Shin, Y.M.; Koo, T.S.; Park, S.J.; Hong, K.B.; Choi, S. A highly sensitive fluorescent probe that quantifies transthyretin in human plasma as an early diagnostic tool of Alzheimer’s disease. Chem. Commun. (Camb.), 2019, 55(70), 10424-10427.
[http://dx.doi.org/10.1039/C9CC04172A] [PMID: 31407744]
[45]
Li, H-Q.; Ip, S-P.; Yuan, Q-J.; Zheng, G-Q.; Tsim, K.K.W.; Dong, T.T.X.; Lin, G.; Han, Y.; Liu, Y.; Xian, Y-F.; Lin, Z.X. Isorhynchophylline ameliorates cognitive impairment via modulating amyloid pathology, tau hyperphosphorylation and neuroinflammation: Studies in a transgenic mouse model of Alzheimer’s disease. Brain Behav. Immun., 2019, 82, 264-278.
[http://dx.doi.org/10.1016/j.bbi.2019.08.194] [PMID: 31476414]
[46]
Zhang, M.Z.; Chen, Q.; Yang, G.F. A review on recent developments of indole-containing antiviral agents. Eur. J. of Med. Chem., 2015, 89, 421-441.
[http://dx.doi.org/10.1016/j.ejmech.2014.10.065]
[47]
Algso, M.A.S.; Kivrak, A.; Konus, M.; Yilmaz, C.; Kurt-Kizildoğan, A. Synthesis and biological evaluation of novel benzothiophene derivatives. J. Chem. Sci., 2018, 130(9), 1-11.
[http://dx.doi.org/10.1007/s12039-018-1523-3]
[48]
Netz, N.; Opatz, T. Marine indole alkaloids. Mar. Drugs, 2015, 13(8), 4814-4914.
[http://dx.doi.org/10.3390/md13084814] [PMID: 26287214]
[49]
Wan, Y.; Li, Y.; Yan, C.; Yan, M.; Tang, Z. Indole: A privileged scaffold for the design of anti-cancer agents. Eur. J. of Med. Chem., 2019, 183, 111691.
[http://dx.doi.org/10.1016/j.ejmech.2019.111691]
[50]
Mondal, A.; Gandhi, A.; Fimognari, C.; Atanasov, A.G.; Bishayee, A. Alkaloids for cancer prevention and therapy: Current progress and future perspectives. Eur. J. Pharmacol., 2019, 858, 172472.
[51]
Soh, Y.; Goto, S.; Kitajima, M.; Moriyama, S.; Kotera, K.; Nakayama, T.; Nakajima, H.; Kondo, T.; Ishimaru, T. Nuclear localisation of glutathione S-transferase π is an evaluation factor for drug resistance in gynaecological cancers. Clin. Oncol. (R. Coll. Radiol.), 2005, 17(4), 264-270.
[http://dx.doi.org/10.1016/j.clon.2004.11.008] [PMID: 15997922]
[52]
Sau, A.; Pellizzari Tregno, F.; Valentino, F.; Federici, G.; Caccuri, A.M. Glutathione transferases and development of new principles to overcome drug resistance. Arch. Biochem. Biophys., 2010, 500(2), 116-122.
[http://dx.doi.org/10.1016/j.abb.2010.05.012] [PMID: 20494652]
[53]
Estevão, M.S.; Carvalho, L.C.; Ribeiro, D.; Couto, D.; Freitas, M.; Gomes, A.; Ferreira, L.M.; Fernandes, E.; Marques, M.M.B. Antioxidant activity of unexplored indole derivatives: Synthesis and screening. Eur. J. Med. Chem., 2010, 45(11), 4869-4878.
[http://dx.doi.org/10.1016/j.ejmech.2010.07.059] [PMID: 20727623]
[54]
Mohamed, M.S.; Youns, M.M.; Ahmed, N.M. Novel indolyl-pyrimidine derivatives: Synthesis, antimicrobial, and antioxidant evaluations. Med. Chem. Res., 2014, 23(7), 3374-3388.
[http://dx.doi.org/10.1007/s00044-014-0916-1]
[55]
Morens, D.M.; Fauci, A.S. Emerging infectious diseases: Threats to human health and global stability. PLoS Pathog., 2013, 9(7), e1003467.
[http://dx.doi.org/10.1371/journal.ppat.1003467] [PMID: 23853589]
[56]
Brown, G.D.; Denning, D.W.; Gow, N.A.R.; Levitz, S.M.; Netea, M.G.; White, T.C. Hidden killers: Human fungal infections. Sci. Transl. Med., 2012, 4(165), 165rv13.
[http://dx.doi.org/10.1126/scitranslmed.3004404] [PMID: 23253612]
[57]
Holland, T.; Fowler, V.G.J.; Shelburne, S.A., 3rd. Invasive Gram-positive bacterial infection in cancer patients. Clin. Infect. Dis. Off. Publ. Infect. Dis. Soc. Am., 2014, 59, S331-S334.
[http://dx.doi.org/10.1093/cid/ciu598]
[58]
El-Sayed, W.A.; Abdel Megeid, R.E.; Abbas, H.A.S. Synthesis and antimicrobial activity of new 1-[(tetrazol-5-yl)methyl] indole derivatives, their 1,2,4-triazole thioglycosides and acyclic analogs. Arch. Pharm. Res., 2011, 34(7), 1085-1096.
[http://dx.doi.org/10.1007/s12272-011-0706-y] [PMID: 21811915]
[59]
Song, M.; Wang, S.; Wang, Z.; Fu, Z.; Zhou, S.; Cheng, H.; Liang, Z.; Deng, X. Synthesis, antimicrobial and cytotoxic activities, and molecular docking studies of N-arylsulfonylindoles containing an aminoguanidine, a semicarbazide, and a thiosemicarbazide moiety. Eur. J. Med. Chem., 2019, 166, 108-118.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.038] [PMID: 30685534]

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