Molecular Diversity

, Volume 19, Issue 4, pp 787–795 | Cite as

Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9(10H)-acridinone-1,2,3-triazoles

  • Maryam Mohammadi-Khanaposhtani
  • Maliheh Safavi
  • Reyhaneh Sabourian
  • Mohammad Mahdavi
  • Mahboobeh Pordeli
  • Mina Saeedi
  • Sussan Kabudanian Ardestani
  • Alireza Foroumadi
  • Abbas Shafiee
  • Tahmineh AkbarzadehEmail author
Full-Length Paper


A new series of 9(10H)-acridinone-1,2,3-triazole derivatives were designed, synthesized and evaluated for their cytotoxic activity against human breast cancer cell lines. The acridone skeleton was prepared through the Ullman condensation of 2-bromobenzoic acid and anilines. Subsequently, it was functionalized with propargyl bromide. Then, a click reaction of the latter compound and in situ prepared 1-(azidomethyl)-4-methoxybenzene derivatives led to the formation of the desired triazole products. Finally, all products were investigated for their capability to cause cytotoxicity against MCF-7, T-47D, and MDA-MB-231 cell lines. Among them, 2-methoxy-10-((1-(4-methoxybenzyl)-1H-1,2,3-triazol-4-yl)methyl)acridin-9(10H)-one 8c exhibited the most potency \((\hbox {IC}_{50}\,{=}\,11.0\,{\pm }\, 4.8\, \upmu \hbox {M})\) against MCF-7 cells, being more potent than etoposide \((\hbox {IC}_{50}\,{=}\, 12.4\,{\pm }\, 4.7 \upmu \hbox {M})\). Also, apoptosis induced by compound 8c was confirmed via acridine orange/ethidium bromide and Annexin V-FITC/propidium iodide (PI) double staining.


Acridone-1, 2, 3-triazoles Cytotoxic activity Click chemistry Breast cancer 



This work was supported by Grant from the Research Council of Tehran University of Medical Sciences under Grant No. 94-01-33-28706.

Supplementary material

11030_2015_9616_MOESM1_ESM.doc (7.4 mb)
Supplementary material 1 (doc 7586 KB)


  1. 1.
    Reddy L, Odhav B, Bhoola KD (2003) Natural products for cancer prevention: a global perspective. Pharmacol Ther 99:1–13. doi: 10.1016/S0163-7258(03)00042-1 CrossRefPubMedGoogle Scholar
  2. 2.
    Fabregat I, Roncero C, Fernandez M (2007) Survival and apoptosis: a dysregulated balance in liver cancer. Liver Int 27:155–162. doi: 10.1111/j.1478-3231.2006.01409.x CrossRefPubMedGoogle Scholar
  3. 3.
    Solary E, Dubrez L, Eymin B (1996) The role of apoptosis in the pathogenesis and treatment of diseases. Eur Respir J 9:1293–1305. doi: 10.1183/09031936.96.09061293 CrossRefPubMedGoogle Scholar
  4. 4.
    Gottesman MM (2002) Mechanisms of cancer drug resistance. Annu Rev Med 53:615–627. doi: 10.1146/ CrossRefPubMedGoogle Scholar
  5. 5.
    Kuno T, Tsukamoto T, Hara A, Tanaka T (2012) Cancer chemoprevention through the induction of apoptosis by natural compounds. J Biophys Chem 3:156–173. doi: 10.4236/jbpc.2012.32018 CrossRefGoogle Scholar
  6. 6.
    Chou CC, Yang JS, Lu HF, Ip SW, Lo C, Wu CC, Lin JP, Tang NY, Chung JG, Chou MJ, Teng YH, Chen DR (2010) Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondria pathway in human breast cancer MCF-7 cells. Arch Pharm Res 33:1181–1191. doi: 10.1007/s12272-010-0808-y CrossRefPubMedGoogle Scholar
  7. 7.
    Kemnitzer W, Sirisoma N, Nguyen B, Jiang S, Kasibhatla S, Crogan-Grundy C, Tseng B, Drewe J, Cai SX (2008) Discovery of 1-benzoyl-3-cyanopyrrolo[1,2-\(a\)]quinolines as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. Part 1: Structure-activity relationships of the 1- and 3-positions. Bioorg Med Chem Lett 18:6259–6264. doi: 10.1016/j.bmcl.2008.09.110 CrossRefPubMedGoogle Scholar
  8. 8.
    Kemnitzer W, Sirisoma N, Nguyen B, Jiang S, Kasibhatla S, Crogan-Grundy C, Tseng B, Drewe J, Cai SX (2009) Discovery of \(N\)-aryl-9-oxo-9\(H\)-fluorene-1-carboxamides as a new series of apoptosis inducers using a cell- and caspase-based high-throughput screening assay. 1. Structure-activity relationships of the carboxamide group. Bioorg Med Chem Lett 19:3045–3049. doi: 10.1016/j.bmcl.2009.04.009 CrossRefPubMedGoogle Scholar
  9. 9.
    Kerr JF, Winterford CM, Harmon BV (1994) Apoptosis. Its significance in cancer and cancer therapy. Cancer 73:2013–2026. doi: 10.1038/nrc2663 CrossRefPubMedGoogle Scholar
  10. 10.
    Cholewiński G, Dzierzbicka K, Kołodziejczyk AM (2011) Natural and synthetic acridines/acridones as antitumor agents: their biological activities and methods of synthesis. Pharmacol Rep 63:305–336. doi: 10.1002/chin.201213236 CrossRefPubMedGoogle Scholar
  11. 11.
    Cao R, Gao CM, Meier H (2005) A facile synthesis of homotriptycenes from anthranol derivatives. Synlett 20:3166–3168. doi: 10.1055/s-2005-921929 CrossRefGoogle Scholar
  12. 12.
    Liu Y, Zou L, Ma L, Chen WH, Wang B, Xu ZL (2006) Synthesis and pharmacological activities of xanthone derivatives as \(\alpha \)-glucosidase inhibitors. Bioorg Med Chem 14:5683–5690. doi: 10.1016/j.bmc.2006.04.014 CrossRefPubMedGoogle Scholar
  13. 13.
    Boumendjel A, Macalou S, Ahmed-Belkacem A, Blanc M, Di Pietro A (2007) Design, synthesis, and inhibition of breast cancer resistance protein ABCG2. Bioorg Med Chem 15:2892–2897. doi: 10.1016/j.bmc.2007.02.017 CrossRefPubMedGoogle Scholar
  14. 14.
    Harrison RJ, Reszka AP, Haider SM, Romagnoli B, Morrell J, Read MA, Gowan SM, Incles CM, Kelland LR, Neidle S (2004) Evaluation of by disubstituted acridone derivatives as telomerase inhibitors: the importance of G-quadruplex binding. Bioorg Med Chem Lett 14:5845–5849. doi: 10.1016/j.bmcl.2004.09.037 CrossRefPubMedGoogle Scholar
  15. 15.
    Dzierzbicka K, Kolodziejczyk AM, Wysocka-Skrzela B, Mysliwski A, Sosnowska D (2001) Synthesis and antitumor activity of conjugates of muramyldipeptide, normuramyldipeptide, and desmuramylpeptides with acridine/acridone derivatives. J Med Chem 44:3606–3615. doi: 10.1021/jm001115g CrossRefPubMedGoogle Scholar
  16. 16.
    Braga PAC, Santos DAPD, Da Silva MFDGF, Vieira PC, Fernandes JB, Houghton PJ, Fang R (2007) In vitro cytotoxicity activity on several cancer cell lines of acridone and \(N\)-phenylethyl-benzamide derivatives from Swingles glutinosa (Bl.) Merr. Nat Prod Res 21:47–55CrossRefPubMedGoogle Scholar
  17. 17.
    Dheyongera JP, Geldenhuys WJ, Dekker TG, Van der Schyf CJ (2005) Synthesis, biological evaluation, and molecular modeling of novel thioacridone derivatives related to the anticancer alkaloid acronycine. Bioorg Med Chem 13:689–698. doi: 10.1016/j.bmc.2004.10.051 CrossRefPubMedGoogle Scholar
  18. 18.
    Cho HJ, Jung MJ, Kwonb Y, Na Y (2009) Oxiranylmethyloxy or thiiranylmethyloxy-azaxanthones and -acridone analogues as potential topoisomerase I inhibitors. Bioorg. Med Chem Lett 19:6766–6769. doi: 10.1016/j.bmcl.2009.09.091 CrossRefPubMedGoogle Scholar
  19. 19.
    Cuenca F, Moore MJB, Johnson K, Guyen B, De Cian A, Neidle S (2009) Design, synthesis and evaluation of 4,5-di-substituted acridone ligands with high G-quadruplex affinity and selectivity, together with low toxicity to normal cells. Bioorg Med Chem Lett 19:5109–5113. doi: 10.1016/j.bmcl.2009.07.033 CrossRefPubMedGoogle Scholar
  20. 20.
    Gao C, Jiang Y, Tan C, Zu X, Liu H, Cao D (2008) Synthesis and potent antileukemic activities of 10-benzyl-9(10\(H)\)-acridinones. Bioorg Med Chem 16:8670–8675. doi: 10.1016/j.bmc.2008.07.086 CrossRefPubMedGoogle Scholar
  21. 21.
    Abboud JLM, Foces-Foces C, Notario R, Trifonov RE, Volovodenko AP, Ostrovskii VA, Alkorta I, Elguero J (2001) Basicity of N-H- and N-Methyl-1,2,3-triazoles in the gas phase, in solution, and in the solid state—an experimental and theoretical study. Eur J Org Chem 16:3013–3024. doi: 10.1002/1099-0690(200108)2001:16<3013::AID-EJOC3013>3.0.CO;2-Y
  22. 22.
    Vatmurge NS, Hazra BG, Pore VS, Shirazi F, Chavan PS, Deshpande MV (2008) Synthesis and antimicrobial activity of \(\beta \)-lactam-bile acid conjugates linked via triazole. Bioorg Med Chem Lett 18:2043–2047. doi: 10.1016/j.bmcl.2008.01.102 CrossRefPubMedGoogle Scholar
  23. 23.
    Lee T, Cho M, Ko SY, Youn HJ, Baek DJ, Cho WJ, Kang CY, Kim S (2007) Synthesis and evaluation of 1,2,3-triazole containing analogues of the immunostimulant \(\alpha \)-GalCer. J Med Chem 50:585–589. doi: 10.1021/jm061243q CrossRefPubMedGoogle Scholar
  24. 24.
    Lewis WG, Green LG, Grynszpan F, Radić Z, Carlier PR, Taylor P, Finn MG, Sharpless KB (2002) Click chemistry in situ: acetylcholinesterase as a reaction vessel for the selective assembly of a femtomolar inhibitor from an array of building blocks. Angew Chem Int Ed Engl 41:1053–1057. doi: 10.1002/1521-3757(20020315)114:6<1095::AID-ANGE1095>3.0.CO;2-3
  25. 25.
    Tron GC, Pirali T, Billington RA, Canoniico PL, Sorba G, Genazzani AA (2008) Click chemistry reactions in medicinal chemistry: applications of the 1,3-dipolar cycloaddition between azides and alkynes. Med Res Rev 28:278–308. doi: 10.1002/med.20107 CrossRefPubMedGoogle Scholar
  26. 26.
    Phillips OA, Udo EE, Abdel-Hamid ME, Varghese R (2009) Synthesis and antibacterial activity of novel 5-(4-methyl-1\(H\)-1,2,3-triazole)methyl oxazolidinones. Eur J Med Chem 44:3217–3227. doi: 10.1016/j.ejmech.2009.03.024 CrossRefPubMedGoogle Scholar
  27. 27.
    Aher NG, Pore VS, Mishra NN, Kumar A, Shukla PK, Sharma A, Bhat MK (2009) Synthesis and antifungal activity of 1,2,3-triazole containing fluconazole analogues. Bioorg Med Chem Lett 19:759–763. doi: 10.1016/j.bmcl.2008.12.026 CrossRefPubMedGoogle Scholar
  28. 28.
    Gill C, Jadhav G, Shaikh M, Kale R, Ghawalkar A, Nagargoje D, Shiradkar M (2008) Clubbed [1,2,3] triazoles by fluorine benzimidazole: a novel approach to H37Rv inhibitors as a potential treatment for tuberculosis. Bioorg Med Chem Lett 18:6244–6247. doi: 10.1016/j.bmcl.2008.09.096 CrossRefPubMedGoogle Scholar
  29. 29.
    Giffin MJ, Heaslet H, Brik A, Lin YC, Cauvi G, Wong CH, McRee DE, Elder JH, Stout CD, Torbett BE (2008) A copper(I)-catalyzed 1,2,3-triazole azide-alkyne click compound is a potent inhibitor of a multidrug-resistant HIV-1 protease variant. J Med Chem 51:6263–6270. doi: 10.1021/jm800149m PubMedCentralCrossRefPubMedGoogle Scholar
  30. 30.
    Tian LJ, Sun YX, Li HJ, Zheng XL, Cheng YZ, Liu XL, Qian BH (2005) Synthesis, characterization and biological activity of triorganotin 2-phenyl-1,2,3-triazole-4-carboxylates. J Inorg Biochem 99:1646–1652. doi: 10.1016/j.jinorgbio.2005.05.006 CrossRefPubMedGoogle Scholar
  31. 31.
    Kim S, Cho M, Lee T, Lee S, Min HY, Lee SK (2007) Design, synthesis, and preliminary biological evaluation of a novel triazole analogue of ceramide. Bioorg Med Chem Lett 17:4584–4587. doi: 10.1016/j.bmcl.2007.05.086 CrossRefPubMedGoogle Scholar
  32. 32.
    Pérez-Tomás R (2006) Multidrug resistance: retrospect and prospects in anti-cancer drug treatment. Curr Med Chem 13:1859–1876. doi: 10.2174/092986706777585077 CrossRefPubMedGoogle Scholar
  33. 33.
    Fallah-Tafti A, Foroumadi A, Tiwari R, Shirazi AN, Hangauer DG, Bu Y, Akbarzadeh T, Parang K, Shafiee A (2011) Thiazolyl \(N\)-benzyl-substituted acetamide derivatives: synthesis, Src kinase inhibitory and anticancer activities. Eur J Med Chem 46:4853–4858. doi: 10.1016/j.ejmech.2011.07.050 CrossRefPubMedGoogle Scholar
  34. 34.
    Fallah-Tafti A, Tiwari R, Shirazi AN, Akbarzadeh T, Mandal D, Shafiee A, Parang K, Foroumadi A (2011) 4-Aryl-4\(H\)-chromene-3-carbonitrile derivatives: evaluation of Src kinase inhibitory and anticancer activities. Med Chem 7:466–472. doi: 10.2174/157340611796799258 CrossRefPubMedGoogle Scholar
  35. 35.
    Motavallizadeh S, Fallah-Tafti A, Maleki S, Shirazi AN, Pordeli M, Safavi M, Ardestani SK, Asd S, Tiwari R, Ohc D, Shafiee A, Foroumadi A, Parang K, Akbarzadeh T (2014) Synthesis and evaluation of antiproliferative activity of substituted \(N\)-xanthen-4-yl)benzenesulfonamides. Tetrahedron Lett 55:373–375. doi: 10.1016/j.tetlet.2013.11.033
  36. 36.
    Mohammadi-Khanaposhtani M, Saeedi M, Zafarghandi NS, Mahdavi M, Sabourian R, Razkenari EK, Alinezhad H, Khanavi M, Foroumadi A, Shafiee A, Akbarzadeh T (2015) Potent acetylcholinesterase inhibitors: design, synthesis, biological evaluation, and docking study of acridone linked to 1,2,3-triazole derivatives. Eur J Med Chem 92:799–806. doi: 10.1016/j.ejmech.2015.01.044
  37. 37.
    Wolf C, Liu S, Mei X, August AT, Casimir M (2006) Regioselective copper-catalyzed amination of bromobenzoic acids using aliphatic and aromatic amines. J Org Chem 71:3270–3273. doi: 10.1021/jo060034a PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Hedge R, Thimmaiah P, Yerigeri MC, Krishnegowda G, Thimmaiah KN, Houghton PJ (2004) Anti-calmodulin acridone derivatives modulate vinblastine resistance in multidrug resistant (MDR) cancer cells. Eur J Med Chem 39:161–178. doi: 10.1016/j.ejmech.2003.12.001 CrossRefGoogle Scholar
  39. 39.
    Mosmann T (1983) Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J Immunol Methods 65:55–63. doi: 10.1016/0022-1759(83)90303-4 CrossRefPubMedGoogle Scholar
  40. 40.
    Safavi M, Esmati N, Ardestani SK, Emami S, Ajdari S, Davoodi J, Shafiee A, Foroumadi A (2012) Halogenated flavanones as potential apoptosis-inducing agents: synthesis and biological activity evaluation. Eur J Med Chem 58:573–580. doi: 10.1016/j.ejmech.2012.10.043 CrossRefPubMedGoogle Scholar
  41. 41.
    Itamochi H, Oishi T, Shimada M, Sato S, Uegaki K, Naniwa J, Sato S, Nonaka M, Terakawa N, Kigawa J, Harada T (2011) Inhibiting the mTOR pathway synergistically enhances cytotoxicity in ovarian cancer cells induced by etoposide through upregulation of c-Jun. Clin Cancer Res 17:4742–4750. doi: 10.1158/1078-0432.CCR-11-0190 CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2015

Authors and Affiliations

  • Maryam Mohammadi-Khanaposhtani
    • 1
  • Maliheh Safavi
    • 2
  • Reyhaneh Sabourian
    • 3
  • Mohammad Mahdavi
    • 4
  • Mahboobeh Pordeli
    • 5
  • Mina Saeedi
    • 6
  • Sussan Kabudanian Ardestani
    • 5
  • Alireza Foroumadi
    • 4
  • Abbas Shafiee
    • 4
  • Tahmineh Akbarzadeh
    • 1
    • 3
    Email author
  1. 1.Department of Medicinal Chemistry, Faculty of PharmacyTehran University of Medical SciencesTehranIran
  2. 2.Department of BiotechnologyIranian Research Organization for Science and TechnologyTehranIran
  3. 3.Persian Medicine and Pharmacy Research CenterTehran University of Medical SciencesTehranIran
  4. 4.Department of Medicinal Chemistry, Faculty of Pharmacy and Pharmaceutical Sciences Research CenterTehran University of Medical SciencesTehranIran
  5. 5.Institute of Biochemistry and Biophysics, Department of BiochemistryUniversity of TehranTehranIran
  6. 6.Medicinal Plants Research Center, Faculty of PharmacyTehran University of Medical SciencesTehranIran

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