Login Register Cart 0
Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Selective Cytotoxic Effects of 5-Trifluoromethoxy-1H-indole-2,3-dione 3-Thiosemicarbazone Derivatives on Lymphoid-originated Cells

Author(s): Ferdane Danışman-Kalındemirtaş*, Serap Erdem-Kuruca, Kadriye Akgün-Dar, Zeynep Karakaş, Özge Soylu and Nilgün Karali

Volume 22, Issue 2, 2022

Published on: 02 March, 2021

Page: [349 - 355] Pages: 7

DOI: 10.2174/1871520621666210302084230

Price: $65

Abstract

Aim: The present study aims to identify the anticancer effect of novel 1H-indole-2,3-dione 3- thiosemicarbazone derivatives. These compounds could be promising anticancer agents in leukemia treatment.

Background: Conventional chemotherapeutic agents accumulate in both normal and tumor cells due to nonspecificity. For effective cancer treatment, new drugs need to be developed to make chemotherapeutics selective for cancer cells. The ultimate goal of cancer treatment is to reduce systemic toxicity and improve the quality of life.

Methods: In this study, the anticancer effects of 5-trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives (A-L) were investigated in chronic myelogenous leukemia K562, Burkitt’s lymphoma P3HR1, acute promyelocytic leukemia HL60 cells, and vincristine-resistant sublines of K562 and P3HR1 cells. Additionally, the compounds were tested on lymphoid-derived cells from ALL patients. In order to investigate the particular mechanism of death caused by the cytotoxic effects of the compounds, immunohistochemical caspase 3 staining was performed in P3HR1 cells, and the resulting apoptotic activities were demonstrated.

Results: All tested compounds have been found to have cytotoxic effects against lymphoma cells at submicromolar concentrations (IC50= 0.89-1.80 μM). Most compounds show significant selectivity for the P3HR1 and P3HR1 Vin resistance. The most effective and selective compound is 4-bromophenyl substituted compound I (IC50=0.96 and 0.89 μM). Cyclohexyl and benzyl substituted compounds D and E have also been found to have cytotoxic effects against K562 cell lines (IC50=2.38 μM), while the allyl substituted compound C is effective on all cell lines (IC50=1.13-2.21 μM). 4-Fluorophenyl substituted F compound has been observed to be effective on all cells (IC50=1.00-2.41 μM) except K562 cell. Compound C is the only compound that shows inhibition of HL-60 cells (IC50= 1.13 μM). Additionally, all compounds exhibited cytotoxic effects on lymphoidderived cells at 1μM concentration. These results are in accordance with the results obtained in lymphoma cells.

Conclusion: All compounds tested have submicromolar concentrations of cytotoxic effects on cells. These compounds hold potential for use in future treatments of leukemia.

Keywords: 5-trifluoromethoxy-1H-indole-2, 3-dione, thiosemicarbazone, cytotoxicity, leukemia, lymphoma, chemotherapy.

« Previous Next »
Graphical Abstract

[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Medvedev, A.; Buneeva, O.; Glover, V. Biological targets for isatin and its analogues: Implications for therapy. Biologics, 2007, 1(2), 151-162.
[PMID: 19707325]
[3]
Lee, D.; Long, S.A.; Adams, J.L.; Chan, G.; Vaidya, K.S.; Francis, T.A.; Kikly, K.; Winkler, J.D.; Sung, C.M.; Debouck, C.; Richardson, S.; Levy, M.A.; DeWolf, W.E., Jr; Keller, P.M.; Tomaszek, T.; Head, M.S.; Ryan, M.D.; Haltiwanger, R.C.; Liang, P.H.; Janson, C.A.; McDevitt, P.J.; Johanson, K.; Concha, N.O.; Chan, W.; Abdel-Meguid, S.S.; Badger, A.M.; Lark, M.W.; Nadeau, D.P.; Suva, L.J.; Gowen, M.; Nuttall, M.E. Potent and selective nonpeptide inhibitors of caspases 3 and 7 inhibit apoptosis and maintain cell functionality. J. Biol. Chem., 2000, 275(21), 16007-16014.
[http://dx.doi.org/10.1074/jbc.275.21.16007] [PMID: 10821855]
[4]
Maillard, M.C.; Dominguez, C.; Gemkow, M.J.; Krieger, F.; Park, H.; Schaertl, S.; Winkler, D.; Muñoz-Sanjuán, I. A label-free LC/MS/MS-based enzymatic activity assay for the detection of genuine caspase inhibitors and SAR development. J. Biomol. Screen., 2013, 18(8), 868-878.
[http://dx.doi.org/10.1177/1087057113492851] [PMID: 23796689]
[5]
Wang, L.J.; Wang, S.Y.; Jiang, B.; Wu, N.; Li, X.Q.; Wang, B.C.; Luo, J.; Yang, M.; Jin, S.H.; Shi, D.Y. Design, synthesis and biological evaluation of novel bromophenol derivatives incorporating indolin-2-one moiety as potential anticancer agents. Mar. Drugs, 2015, 13(2), 806-823.
[http://dx.doi.org/10.3390/md13020806] [PMID: 25648512]
[6]
Zhenodarova, S.M. Small-molecule caspase inhibitors. Russ. Chem. Rev., 2010, 79(2), 119.
[http://dx.doi.org/10.1070/RC2010v079n02ABEH004056]
[7]
Okun, I.; Balakin, K.V.; Tkachenko, S.E.; Ivachtchenko, A.V. Caspase activity modulators as anticancer agents.Anti-Cancer Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry-Anti-Cancer Agents), 2008, 8(3), 322-341.,
[8]
Attia, M.I.; Eldehna, W.M.; Afifi, S.A.; Keeton, A.B.; Piazza, G.A.; Abdel-Aziz, H.A. New hydrazonoindolin-2-ones: Synthesis, exploration of the possible anti-proliferative mechanism of action and encapsulation into PLGA microspheres. PLoS One, 2017, 12(7)e0181241
[http://dx.doi.org/10.1371/journal.pone.0181241] [PMID: 28742842]
[9]
Al-Wabli, R.I.; Almomen, A.A.; Almutairi, M.S.; Keeton, A.B.; Piazza, G.A.; Attia, M.I. New Isatin-Indole Conjugates: Synthesis, Characterization, and a Plausible Mechanism of Their in vitro Antiproliferative Activity. Drug Des. Devel. Ther., 2020, 14(14), 483-495.
[http://dx.doi.org/10.2147/DDDT.S227862] [PMID: 32099332]
[10]
Pervez, H.; Saira, N.; Iqbal, M.S.; Yaqub, M.; Khan, K.M. Synthesis and toxicity evaluation of some N4-aryl substituted 5-trifluoromethoxyisatin-3-thiosemicarbazones. Molecules, 2011, 16(8), 6408-6421.
[http://dx.doi.org/10.3390/molecules16086408] [PMID: 25134761]
[11]
Pervez, H.; Saira, N.; Iqbal, M.S.; Yaqub, M.; Khan, K.M. Synthesis and biological evaluation of some N 4-aryl-substituted 5-fluoroisatin-3-thiosemicarbazones. Med. Chem. Res., 2013, 22(12), 5878-5889.
[http://dx.doi.org/10.1007/s00044-013-0575-7]
[12]
Lin, H.H.; Wu, W.Y.; Cao, S.L.; Liao, J.; Ma, L.; Gao, M.; Li, Z.F.; Xu, X. Synthesis and antiproliferative evaluation of piperazine-1-carbothiohydrazide derivatives of indolin-2-one. Bioorg. Med. Chem. Lett., 2013, 23(11), 3304-3307.
[http://dx.doi.org/10.1016/j.bmcl.2013.03.099] [PMID: 23602441]
[13]
Karali, N. Synthesis and primary cytotoxicity evaluation of new 5-nitroindole-2,3-dione derivatives. Eur. J. Med. Chem., 2002, 37(11), 909-918.
[http://dx.doi.org/10.1016/S0223-5234(02)01416-2] [PMID: 12446050]
[14]
Karali, N.; Terzioğlu, N.; Gürsoy, A. Synthesis and primary cytotoxicity evaluation of new 5-bromo-3-substituted-hydrazono-1H-2-indolinones. Arch. Pharm. (Weinheim), 2002, 335(8), 374-380.
[http://dx.doi.org/10.1002/1521-4184(200211)335:8<374:AID-ARDP374>3.0.CO;2-K] [PMID: 12397621]
[15]
Hall, M.D.; Salam, N.K.; Hellawell, J.L.; Fales, H.M.; Kensler, C.B.; Ludwig, J.A.; Szakács, G.; Hibbs, D.E.; Gottesman, M.M. Synthesis, activity, and pharmacophore development for isatin-β-thiosemicarbazones with selective activity toward multidrug-resistant cells. J. Med. Chem., 2009, 52(10), 3191-3204.
[http://dx.doi.org/10.1021/jm800861c] [PMID: 19397322]
[16]
Hall, M.D.; Brimacombe, K.R.; Varonka, M.S.; Pluchino, K.M.; Monda, J.K.; Li, J.; Walsh, M.J.; Boxer, M.B.; Warren, T.H.; Fales, H.M.; Gottesman, M.M. Synthesis and structure-activity evaluation of isatin-β-thiosemicarbazones with improved selective activity toward multidrug-resistant cells expressing P-glycoprotein. J. Med. Chem., 2011, 54(16), 5878-5889.
[http://dx.doi.org/10.1021/jm2006047] [PMID: 21721528]
[17]
Pape, V.F.; Tóth, S.; Füredi, A.; Szebényi, K.; Lovrics, A.; Szabó, P.; Wiese, M.; Szakács, G. Design, synthesis and biological evaluation of thiosemicarbazones, hydrazinobenzothiazoles and arylhydrazones as anticancer agents with a potential to overcome multidrug resistance. Eur. J. Med. Chem., 2016, 117, 335-354.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.078] [PMID: 27161177]
[18]
Güzel, O.; Karali, N.; Salman, A. Synthesis and antituberculosis activity of 5-methyl/trifluoromethoxy-1H-indole-2,3-dione 3-thiosemicarbazone derivatives. Bioorg. Med. Chem., 2008, 16(19), 8976-8987.
[http://dx.doi.org/10.1016/j.bmc.2008.08.050] [PMID: 18804379]
[19]
Hokland, P.; Heron, I. Analysis of the lymphocyte distribution during Isopaque-Ficoll isolation of mononuclear cells from human peripheral blood. J. Immunol. Methods, 1980, 32(1), 31-39.
[http://dx.doi.org/10.1016/0022-1759(80)90114-3] [PMID: 7351482]
[20]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[21]
Engin, K.N.; Erdem-Kuruca, S.; Akgün-Dar, K.; Çetin, B.; Karadenizli, S.; Gürel, E.; Yemisci, B.; Bilgiç, S.; Arslan, M. The evaluation of human tenon’s fibroblasts and endothelial cell responses to antifibrotics alone and in combination with α-tocopherol.Curr. Eye Res., 2015, 40(1), 19-29.,
[http://dx.doi.org/10.3109/02713683.2014.909496] [PMID: 24750068]

Rights & Permissions Print Cite
Article Metrics
27
3
© 2024 Bentham Science Publishers | Privacy Policy