Design, Synthesis and Biological Evaluation of 1H-1,2,3-Triazole-Linked-1H-Dibenzo[b,h]xanthenes as Inductors of ROS-Mediated Apoptosis in the Breast Cancer Cell Line MCF-7

Author(s): Carolina S. Bortolot, Luana da S.M. Forezi, Roberta K.F. Marra, Marcelo I.P. Reis, Bárbara V.F.e Sá, Ricardo I. Filho, Zeinab Ghasemishahrestani, Mauro Sola-Penna, Patricia Zancan, Vitor F. Ferreira*, Fernando de C. da Silva*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 2 , 2019

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Graphical Abstract:


Background: Low molecular weight 1,2,3-triazoles and naphthoquinones are endowed with various types of biological activity, such as against cancer, HIV and bacteria. However, in some cases, the conjugation of these two nuclei considerably increases their biological activities.

Objective: In this work, we decided to study the synthesis and screening of bis-naphthoquinones and xanthenes tethered to 1,2,3-triazoles against cancer cell lines, specifically the human breast cancer cell line MCF-7.

Results: Starting from lawsone and aryl-1H-1,2,3-triazole-4-carbaldehydes (10a-h) several new 7- (1-aryl-1H-1,2,3-triazol-4-yl)-6H-dibenzo[b,h]xanthene-5,6,8,13(7H)-tetraones (12a-h) and 3,3'- ((1-aryl-1H-1,2,3-triazol-4-yl)methylene)bis(2-hydroxynaphthalene-1,4-diones) 11a-h were synthesized and evaluated for their cytotoxic activities using the human breast cancer cell line MCF-7 and the non-tumor cell line MCF10A as control. We performed test of cell viability, cell proliferation, intracellular ATP content and cell cytometry to determine reactive oxygen species (ROS) formation.

Conclusions: Based on these results, we found that compound 12a promotes ROS production, interfering with energy metabolism, cell viability and proliferation, and thus promoting whole cell damage.

Keywords: Cell viability, naphthoquinones, lawsone, MTT assay, ATP, CyQuant assay.

da Silva, F.C.; Ferreira, V.F. Natural naphthoquinones with great importance in medicinal chemistry. Curr. Org. Synth., 2016, 13, 334-371.
Salmon-Chemin, L.; Buisine, E.; Yardley, V.; Kohler, S.; Debreu, M.A.; Landry, V.; Sergheraert, C.; Croft, S.L.; Krauth-Siegel, R.L.; Davioud-Charvet, E. 2- and 3-substituted 1,4-naphthoquinone derivatives as subversive substrates of trypanothione reductase and lipoamide dehydrogenase from Trypanosoma cruzi: synthesis and correlation between redox cycling activities and in vitro cytotoxicity. J. Med. Chem., 2001, 44, 548-565.
Müller, T.; Johann, L.; Jannack, B.; Brückner, M.; Lanfranchi, D.A.; Bauer, H.; Sanchez, C.; Yardley, V.; Deregnaucourt, C.; Schrével, J.; Lanzer, M.; Schirmer, R.H.; Davioud-Charvet, E. Glutathione reductase-catalyzed cascade of redox reactions to bioactivate potent antimalarial 1,4-naphthoquinones-a new strategy to combat malarial parasites. J. Am. Chem. Soc., 2011, 133, 11557-11571.
Benites, J.; Valderrama, J.A.; Rivera, F.; Rojo, L.; Campos, N.; Pedro, M.; José Nascimento, M.S. Studies on quinones. Part 42: Synthesis of furylquinone and hydroquinones with antiproliferative activity against human tumor cell lines. Bioorg. Med. Chem., 2008, 16, 862-868.
Silva, M.N.; de Souza, M.C.B.V.; Ferreira, V.F.; Pinto, A.V.; Pinto, M.C.R.F.; Wardell, S.M.S.V.; Wardell, J.L. Synthesis of new aldehyde derivatives from β-lapachone and nor-β-lapachone. ARKIVOC, 2003, 156-168.
Yang, R.Y.; Kizer, D.; Wu, H.; Volckova, E.; Miao, X.S.; Ali, S.M.; Tandon, M.; Savage, R.E.; Chan, T.C.; Ashwell, M.A. Synthetic methods for the preparation of ARQ 501 (beta-Lapachone) human blood metabolites. Bioorg. Med. Chem., 2008, 16, 5635-5643.
Khong, H.T.; Dreisbach, L.; Kindler, H.L.; Trent, D.F.; Jeziorski, K.G.; Bonderenko, I.; Popiela, T.; Yagovane, D.M.; Dombal, G. A phase 2 study of ARQ 501 in combination with gemcitabine in adult patients with treatment naïve, unresectable pancreatic adenocarcinoma. J. Clin. Oncol., 2007, 25, 15017.
ArQule, Inc.ArQule presents preliminary interim phase 1 data for ARQ 501 and announces combination study with taxotere. PR Newswire. Available at:. html 2004 (Accessed 27.07.17).
Cragg, G.M.; Grothaus, P.G.; Newman, D.J. New horizons for old drugs and drug leads. J. Nat. Prod., 2014, 77, 703-723.
da Costa, E.C.B.; Amorim, R.; da Silva, F.C.; Papa, M.P.; de Arruda, L.B.; Mohana-Borges, R.; Ferreira, V.F.; Tanuri, A.; da Costa, L.J.; Ferreira, S.B. Synthetic 1,4-pyran naphthoquinones are potent inhibitors of dengue virus replication. PLoS One, 2013, 8, e82504.
Moosophon, P.; Kanokmedhakul, S.; Kanokmedhakul, K.; Soytong, K. Prenylxanthones and a bicyclo[3.3.1]nona-2,6-diene derivative from the fungus Emericella rugulosa. J. Nat. Prod., 2009, 72, 1442-1446.
Hay, A.E.; Aumond, M.C.; Mallet, S.; Dumontet, V.; Litaudon, M.; Rondeau, D.; Richomme, P. Antioxidant xanthones from Garcinia vieillardii. J. Nat. Prod., 2004, 67, 707-709.
Hashim, N.; Rahmani, M.; Sukari, M.A.; Ali, A.M.; Alitheen, N.B.; Go, R.; Ismail, H.B. Two new xanthones from Artocarpus obtusus. J. Asian Nat. Prod. Res., 2010, 12, 106-112.
Jamison, J.M.; Krabill, K.; Hatwalkar, A.; Jamison, E.; Tsai, C.C. Potentiation of the antiviral activity of poly r(A-U) by xanthene dyes. Cell Biol. Int. Rep., 1990, 14, 1075-1084.
Evangelinou, O.; Hatzidimitriou, A.G.; Velali, E.; Pantazaki, A.A.; Voulgarakis, N.; Aslanidis, P. Mixed-ligand copper(I) halide complexes bearing 4,5-bis(diphenylphosphano)-9,9-dimethyl-xanthene and N-methylbenzothiazole-2-thione: Synthesis, structures, luminescence and antibacterial activity mediated by DNA and membrane damage. Polyhedron, 2014, 72, 122-129.
Yunnikova, L.P.; Gorokhov, V.Y.; Makhova, T.V.; Aleksandrova, G.A. Synthesis and Antimicrobial Activity of Amines with Azaxanthene Fragments. Pharm. Chem. J., 2013, 47, 139-141.
Azebaze, A.G.; Meyer, M.; Valentin, A.; Nguemfo, E.L.; Fomum, Z.T.; Nkengfack, A.E. Prenylated xanthone derivatives with antiplasmodial activity from Allanblackia monticola STANER L.C. Chem. Pharm. Bull. , 2006, 54, 111-113.
Zelefack, F.; Guilet, D.; Fabre, N.; Bayet, C.; Chevalley, S.; Ngouela, S.; Lenta, B.N.; Valentin, A.; Tsamo, E.; Dijoux-Franca, M.G. Cytotoxic and antiplasmodial xanthones from Pentadesma butyracea. J. Nat. Prod., 2009, 72, 954-957.
Laphookhieo, S.; Syers, J.K.; Kiattansakul, R.; Chantrapromma, K. Cytotoxic and antimalarial prenylated xanthones from Cratoxylum cochinchinense. Chem. Pharm. Bull. (Tokyo), 2006, 54, 745-747.
Djoufack, G.L.; Valant-Vetschera, K.M.; Schinnerl, J.; Brecker, L.; Lorbeer, E.; Robien, W. Xanthones, biflavanones and triterpenes from Pentadesma grandifolia (Clusiaceae): structural determination and bioactivity. Nat. Prod. Commun., 2010, 5, 1055-1060.
Poupelin, J.P.; Saint-Ruf, G.; Foussard-Blanpin, O.; Narcisse, G.; Uchida-Ernouf, G.; Lacroix, R. Synthesis and antiinflammatory properties of bis (2-hydroxy-1-naphthyl)methane derivatives I. Eur. J. Med. Chem., 1978, 13, 67-71.
Rewcastle, G.W.; Atwell, G.J.; Li, Z.A.; Baguley, B.C.; Denny, W.A. Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among disubstituted 9-oxo-9H-xanthene-4-acetic acids. J. Med. Chem., 1991, 34, 217-222.
Niu, S.L.; Li, Z.L.; Ji, F.; Liu, G.Y.; Zhao, N.; Liu, X.Q.; Jing, Y.K.; Hua, H.M. Xanthones from the stem bark of Garcinia bracteata with growth inhibitory effects against HL-60 cells. Phytochemistry, 2012, 77, 280-286.
Lee, K.H.; Chai, H.B.; Tamez, P.A.; Pezzuto, J.M.; Cordell, G.A.; Win, K.K.; Tin-Wa, M. Biologically active alkylated coumarins from Kayea assamica. Phytochemistry, 2003, 64, 535-541.
Tao, S.J.; Guan, S.H.; Wang, W.; Lu, Z.Q.; Chen, G.T.; Sha, N.; Yue, Q.X.; Liu, X.; Guo, D.A. Cytotoxic polyprenylated xanthones from the resin of Garcinia hanburyi. J. Nat. Prod., 2009, 72, 117-124.
Diniz, T.F.; Pereira, A.C.; Capettini, L.S.A.; Santos, M.H.; Nagem, T.J.; Lemos, V.S.; Cortes, S.F. Mechanism of the vasodilator effect of mono-oxygenated xanthones: a structure-activity relationship study. Planta Med., 2013, 79, 1495-1500.
Rao, T.V.P.; Venkateswarlu, V. Chemical examination of embelia ribes-VI: Synthesis of some new methylene-bisbenzoquinones. Tetrahedron, 1964, 20, 2967-2970.
Tisseh, Z.N.; Azimi, S.C.; Mirzaei, P.; Bazgir, A. The efficient synthesis of aryl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-tetraone leuco-dye derivatives. Dyes Pigments, 2008, 79, 273-275.
Tavakoli, H.R.; Moosavi, S.M.; Bazgir, A. ZrOCl2•8H2O as an efficient catalyst for the synthesis of dibenzo [b,i]xanthene-tetraones and fluorescent hydroxyl naphthalene-1,4-diones. Res. Chem. Intermed., 2015, 41, 3041-3046.
Chen, Y.; Wu, S.; Tu, S.; Li, C.; Shi, F. A simple procedure for the synthesis of benzoxanthene derivatives under microwave irradiation conditions. J. Heterocycl. Chem., 2008, 45, 931-934.
Shaterian, H.R.; Azizi, K.; Fahimi, N. Phosphoric acid supported on alumina (H3PO4/Al2O3) as an efficient and reusable catalyst for the one-pot synthesis of benzoxanthene pigments. Res. Chem. Intermed., 2014, 40, 1403-1414.
Shaterian, H.R.; Rigi, F. An efficient synthesis of quinazoline and xanthene derivatives using starch sulfate as a biodegradable solid acid catalyst. Res. Chem. Intermed., 2015, 41, 721-738.
Amini, M.M.; Fazaeli, Y.; Yassaee, Z.; Shahzad, F.; Ayoob, B. Polytungstozincate Acid: A new and efficient catalyst for the synthesis of xanthenes under solvent-free conditions. Open Catal. J., 2009, 2, 40-44.
Khaligh, N.G. Poly(4-vinylpyridinium) hydrogen sulfate: an efficient catalyst for the synthesis of xanthene derivatives under solvent-free conditions. Catal. Sci. Technol., 2012, 2, 2211-2215.
Liu, D.; Gao, J.; Li, L.; Zhou, S.; Xu, D. Silica-supported sodium hydrogen sulfate catalyzed synthesis of 13-aryl-12h-dibenzo[b,i]-xanthene-5,7,12,14(13h)-tetraones. Chem. Heterocycl. Compd., 2013, 49, 1370-1373.
Shaterian, H.R.; Sedghipour, M.; Mollashahi, E. Brønsted acidic ionic liquids catalyzed the preparation of 13-aryl-5H-dibenzo[b,i]xanthene-5,7,12,14(13H)-tetraones and 3,4-dihydro-1H-benzo[b]xanthene-1,6,11(2H,12H)-triones. Res. Chem. Intermed., 2014, 40, 1345-1355.
Bazgir, A.; Tisseh, Z.N.; Mirzaei, P. An efficient synthesis of spiro[dibenzo[b,i]xanthene-13,3′-indoline]-pentaones and 5H-dibenzo[b,i]xanthene-tetraones. Tetrahedron Lett., 2008, 49, 5165-5168.
Carneiro, P.F.; Pinto, M.C.F.R.; Marra, R.K.F.; Campos, V.R.; Resende, J.A.; Delarmelina, M.; Carneiro, J.W.; Lima, E.S.; da Silva, F.C.; Ferreira, V.F. Insight into and Computational Studies of the Selective Synthesis of 6H-Dibenzo[b,h]xanthenes. J. Org. Chem., 2016, 81, 5525-5537.
Ferreira, V.F.; Nicoletti, C.D.; Ferreira, P.G.; Futuro, D.O.; da Silva, F.C. Strategies for increasing the solubility and bioavailability of anticancer compounds: β-Lapachone and other naphthoquinones. Curr. Pharm. Des., 2016, 22, 5899-5914.
Cardoso, M.F.C.; Rodrigues, P.C.; Oliveira, M.E.I.M.; Gama, I.L.; da Silva, I.M.; Santos, I.O.; Rocha, D.R.; Pinho, R.T. Ferreira, V.F.; de Souza M.C.; da Silva, F. C.; Silva-Jr, F.P. Synthesis and evaluation of the cytotoxic activity of 1,2-furanonaphthoquinones tethered to 1,2,3-1H-triazoles in myeloid and lymphoid leukemia cell lines. Eur. J. Med. Chem., 2014, 84, 708-717.
Zancan, P.; Sola-Penna, M.; Furtado, C.M.; da Silva, D. Differential expression of phosphofructokinase-1 isoforms correlates with the glycolytic efficiency of breast cancer cells. Mol. Genet. Metab., 2010, 100, 372-378.
Spitz, G.A.; Furtado, C.M.; Sola-Penna, M.; Zancan, P. Acetylsalicylic acid and salicylic acid decrease tumor cell viability and glucose metabolism modulating 6-phosphofructo-1-kinase structure and activity. Biochem. Pharmacol., 2009, 77, 46-53.
Furtado, C.M.; Marcondes, M.C.; Sola-Penna, M.; de Souza, M.L.; Zancan, P. Clotrimazole Preferentially Inhibits Human Breast Cancer Cell Proliferation, Viability and Glycolysis. PLoS One, 2012, 7, e30462.
Boechat, N.; Ferreira, V.F.; Ferreira, S.B. M.L.G., Ferreira; F.C., da Silva; Bastos, M.M.; Costa, M.S.; Lourenço, M.C.; Pinto, A.C.; Krettli, A.U.; Aguiar, A.C.; Teixeira, B.M.; da Silva, N.V.; Martins, P.R.; Bezerra, F.A.; Camilo, A.L.; da Silva, G.P.; Costa, C.C. Novel 1,2,3-Triazole Derivatives for Use against Mycobacterium tuberculosis H37Rv (ATCC 27294). Strain. J. Med. Chem., 2011, 54, 5988-5999.
da Silva, I.F.; Martins, P.R.C.; da Silva, E.G.; Ferreira, S.B.; Ferreira, V.F.; da Costa, K.R.; de Vasconcellos, M.C.; Lima, E.S.; da Silva, F.C. Synthesis of 1H-1,2,3-triazoles and Study of their Antifungal and Cytotoxicity Activities. Med. Chem., 2013, 9, 1085-1090.
Gao, S.Y.; Gong, Y.F.; Sun, Q.J.; Bai, J.; Wang, L.; Fan, Z.Q.; Sun, Y.; Su, Y.J.; Gang, J.; Ji, Y.B. Screening antitumor bioactive fraction from Sauromatum giganteum (Engl.) Cusimano & Hett and sensitive cell lines with the serum pharmacology method and identification by UPLC-TOF-MS. Molecules, 2015, 20, 4290-4306.
Zhang, N.; Guo, H.; Zheng, W.; Wang, T.; Ma, X. Design and screening of a chimeric survivin-specific nanobody and its anticancer activities in vitro. Anticancer Drugs, 2016, 27, 839-847.
Musumeci, D.; Amato, J.; Zizza, P.; Platella, C.; Cosconati, S.; Cingolani, C.; Biroccio, A.; Novellino, E.; Randazzo, A.; Giancola, C.; Pagano, B.; Montesarchio, D. Tandem application of ligand-based virtual screening and G4-OAS assay to identify novel G-quadruplex-targeting chemotypes. Biochim. Biophys. Acta, 2017, 1861, 1341-1352.
Tam, K.F.; Ng, T.Y.; Tsang, P.C.; Li, C.F.; Ngan, H.Y. Potential use of the adenosine triphosphate cell viability assay in endometrial cancer. J. Soc. Gynecol. Investig., 2006, 13, 518-522.
Pointon, A.V.; Walker, T.M.; Phillips, K.M.; Luo, J.; Riley, J.; Zhang, S.D.; Parry, J.D.; Lyon, J.J.; Marczylo, E.L.; Gant, T.W. Doxorubicin in vivo rapidly alters expression and translation of myocardial electron transport chain genes, leads to ATP loss and caspase 3 activation. PLoS One, 2010, 5, e12733.
Bean, J.F.; Qiu, Y.Y.; Yu, S.; Clark, S.; Chu, F.; Madonna, M.B. Glycolysis inhibition and its effect in doxorubicin resistance in neuroblastoma. J. Pediatr. Surg., 2014, 49, 981-984.
Jones, L.J.; Gray, M.; Yue, S.T.; Haugland, R.P.; Singer, V.L. Sensitive determination of cell number using the CyQUANT cell proliferation assay. J. Immunol. Methods, 2001, 254, 85-98.
Lee, Y.; Oh, S.B.; Park, H.R.; Kim, H.S.; Kim, M.S.; Lee, J. Selective impairment on the proliferation of neural progenitor cells by oxidative phosphorylation disruption. Neurosci. Lett., 2013, 535, 134-139.
Park, W.H.; You, B.R. Antimycin A induces death of the human pulmonary fibroblast cells via ROS increase and GSH depletion. Int. J. Oncol., 2016, 48, 813-820.

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Year: 2019
Page: [119 - 129]
Pages: 11
DOI: 10.2174/1573406414666180524071409
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