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

In Vitro Cytotoxicity and Apoptosis Inducing Evaluation of Novel Halogenated Isatin Derivatives

Author(s): Hadi Adibi, Ehsan Beyhaghi, Sonya Hayati, Leila Hosseinzadeh* and Niloufar Amin*

Volume 22, Issue 13, 2022

Published on: 17 March, 2022

Page: [2439 - 2447] Pages: 9

DOI: 10.2174/1871520622666220119091642

Price: $65

Abstract

Background: Isatin (1H-indole-2,3-dione) and its derivatives have been utilized in a variety of biological activities. Anticancer compounds were the most extensively highlighted and explored among the range of beneficial properties.

Objective: Herein, we report the targeting effect of halogenated isatin derivatives on cancer cell mitochondria and their antiproliferative mechanism.

Methods: A series of novel 5-halo-Isatin derivatives consisting of the 5-Amino-1,3,4-thiadiazole-2-thiol scaffold were synthesized and easily conducted in good yields through a condensation reaction between keto groups of Isatin and primary amine under alcoholic conditions, followed by S-benzylation. The compounds were fully characterized using spectroscopic methods such as 1H-NMR, FTIR, mass spectroscopy and then tested in vitro towards three cancer cell lines HT-29 (colon cancer), MCF-7 (breast cancer), and SKNMC (neuroblastoma). Apoptosis induction was investigated through assessment of caspase 3 and mitochondrial membrane potential.

Results: The most potent compounds of 5b, 5r (IC50 = 18,13 μM), and 5n (IC50 = 20,17 μM) were found to show strong anticancer activity, especially for MCF7 cells. Further anticancer mechanism studies indicated that 5b and 5r induced apoptosis through the intrinsic mitochondrial pathway.

Conclusion: This research demonstrated that 5b and 5r have an anticancer property via the modulation of oxidative stress-mediated mitochondrial apoptosis and immune response, which deserves further studies on their clinical applications.

Keywords: Isatin, 1, 3, 4-thiadiazole, cytotoxicity, apoptosis, biological activity, antitumor activities.

« Previous Next »
Graphical Abstract

[1]
Oun, R.; Moussa, Y.E.; Wheate, N.J. Correction: The side effects of platinum-based chemotherapy drugs: a review for chemists. Dalton Trans., 2018, 47(23), 7848.
[http://dx.doi.org/10.1039/C8DT90088D] [PMID: 29808879]
[2]
Staff, N.P.; Grisold, A.; Grisold, W.; Windebank, A.J. Chemotherapy-induced peripheral neuropathy: A current review. Ann. Neurol., 2017, 81(6), 772-781.
[http://dx.doi.org/10.1002/ana.24951] [PMID: 28486769]
[3]
Kamal, A.; Srinivasa Reddy, T.; Polepalli, S.; Paidakula, S.; Srinivasulu, V.; Ganga Reddy, V.; Jain, N.; Shankaraiah, N. Synthesis and biological evaluation of 4-aza-2,3-dihydropyridophenanthrolines as tubulin polymerization inhibitors. Bioorg. Med. Chem. Lett., 2014, 24(15), 3356-3360.
[http://dx.doi.org/10.1016/j.bmcl.2014.05.096] [PMID: 24953821]
[4]
Rashid, M.; Husain, A.; Mishra, R. Synthesis of benzimidazoles bearing oxadiazole nucleus as anticancer agents. Eur. J. Med. Chem., 2012, 54, 855-866.
[http://dx.doi.org/10.1016/j.ejmech.2012.04.027] [PMID: 22608854]
[5]
Arjomandi, O.K.; Almasi, S.; Hosseinzadeh, L.; Kavoosi, M.; Adibi, H. Preparation, characterization and in vitro biological evaluation of novel curcumin derivatives as cytotoxic and apoptosis-inducing agents. Anticancer. Agents Med. Chem., 2021, 21(10), 1309-1322.
[http://dx.doi.org/10.2174/1871520620666201002111205] [PMID: 33006540]
[6]
Hosseinzadeh; >Mahmoudian, N.; Ahmadi, F.; Adibi, H. Synthesis of 4-Phenyl-4,5-Dihydropyranopyrazolone derivatives with activated potassium carbonate: Evalua-tion of anticancer activity on cancer cell lines and apoptosis mechanism. J. Reports Pharm. Sci., 2019, 8(2), 262.
[http://dx.doi.org/10.4103/jrptps.JRPTPS_82_19]
[7]
Bahrami; Hosseinzadeh, L.; Azadi, Z.; Mohammadi, B.; Mahdiyan, Z.; Hajialyani, M.; Farzaei, M. H The anti-atherosclerotic effect of Prosopis Farcta is associated with the inhibition of VCAM-1 and ICAM-1. J. Reports Pharm. Sci., 2021, 7(3), 357.
[8]
Hassan, A.H.E.; Choi, E.; Yoon, Y.M.; Lee, K.W.; Yoo, S.Y.; Cho, M.C.; Yang, J.S.; Kim, H.I.; Hong, J.Y.; Shin, J.S.; Chung, K.S.; Lee, J.H.; Lee, K.T.; Lee, Y.S. AHE. Natural products hybrids: 3,5,4′-Trimethoxystilbene-5,6,7-trimethoxyflavone chimeric analogs as potential cytotoxic agents against diverse human cancer cells. Eur. J. Med. Chem., 2019, 161, 559-580.
[http://dx.doi.org/10.1016/j.ejmech.2018.10.062] [PMID: 30396104]
[9]
Melis, C.; Meleddu, R.; Angeli, A.; Distinto, S.; Bianco, G.; Capasso, C.; Cottiglia, F.; Angius, R.; Supuran, C.T.; Maccioni, E. Isatin: a privileged scaffold for the design of carbonic anhydrase inhibitors. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 68-73.
[http://dx.doi.org/10.1080/14756366.2016.1235042] [PMID: 27775452]
[10]
Da Silva, J.F.M.; Garden, S.J.; Pinto, A.C. The chemistry of isatins: A review from 1975 to 1999. J. Braz. Chem., 2001, 12(3), 273-324.
[http://dx.doi.org/10.1590/S0103-50532001000300002]
[11]
Pandeya, S.N.; Smitha, S.; Jyoti, M.; Sridhar, S.K. Biological activities of isatin and its derivatives. Acta Pharm., 2005, 55(1), 27-46.
[PMID: 15907222]
[12]
Pandeya, S.N.; Sriram, D.; Nath, G.; DeClercq, E. Synthesis, antibacterial, antifungal and anti-HIV activities of Schiff and Mannich bases derived from isatin derivatives and N-[4-(4′-chlorophenyl)thiazol-2-yl] thiosemicarbazide. Eur. J. Pharm. Sci., 1999, 9(1), 25-31.
[http://dx.doi.org/10.1016/S0928-0987(99)00038-X] [PMID: 10493993]
[13]
Zapata-Sudo, G.; Pontes, L.B.; Gabriel, D.; Mendes, T.C.F.; Ribeiro, N.M.; Pinto, A.C.; Trachez, M.M.; Sudo, R.T. Sedative-hypnotic profile of novel isatin ketals. Pharmacol. Biochem. Behav., 2007, 86(4), 678-685.
[http://dx.doi.org/10.1016/j.pbb.2007.02.013] [PMID: 17382995]
[14]
Radi, M.; Crespan, E.; Botta, G.; Falchi, F.; Maga, G.; Manetti, F.; Corradi, V.; Mancini, M.; Santucci, M.A.; Schenone, S.; Botta, M. Discovery and SAR of 1,3,4-thiadiazole derivatives as potent Abl tyrosine kinase inhibitors and cytodifferentiating agents. Bioorg. Med. Chem. Lett., 2008, 18(3), 1207-1211.
[http://dx.doi.org/10.1016/j.bmcl.2007.11.112] [PMID: 18078752]
[15]
Solomon, V.R.; Hu, C.; Lee, H. Hybrid pharmacophore design and synthesis of isatin-benzothiazole analogs for their anti-breast cancer activity. Bioorg. Med. Chem., 2009, 17(21), 7585-7592.
[http://dx.doi.org/10.1016/j.bmc.2009.08.068] [PMID: 19804979]
[16]
Nithinchandra; Kalluraya, B.; Aamir, S.; Shabaraya, A.R. Regioselective reaction: synthesis, characterization and pharmacological activity of some new Mannich and Schiff bases containing sydnone. Eur. J. Med. Chem., 2012, 54, 597-604.
[http://dx.doi.org/10.1016/j.ejmech.2012.06.011] [PMID: 22795833]
[17]
Kumar, D.; Vaddula, B.R.; Chang, K.H.; Shah, K. One-pot synthesis and anticancer studies of 2-arylamino-5-aryl-1,3,4-thiadiazoles. Bioorg. Med. Chem. Lett., 2011, 21(8), 2320-2323.
[http://dx.doi.org/10.1016/j.bmcl.2011.02.083] [PMID: 21429743]
[18]
Rzeski, W.; Matysiak, J. Kandefer-Szerszeń M. Anticancer, neuroprotective activities and computational studies of 2-amino-1,3,4-thiadiazole based compound. Bioorg. Med. Chem., 2007, 15(9), 3201-3207.
[http://dx.doi.org/10.1016/j.bmc.2007.02.041] [PMID: 17350846]
[19]
Yang, X.H.; Wen, Q.; Zhao, T.T.; Sun, J.; Li, X.; Xing, M.; Lu, X.; Zhu, H.L. Synthesis, biological evaluation, and molecular docking studies of cinnamic acyl 1,3,4-thiadiazole amide derivatives as novel antitubulin agents. Bioorg. Med. Chem., 2012, 20(3), 1181-1187.
[http://dx.doi.org/10.1016/j.bmc.2011.12.057] [PMID: 22261027]
[20]
Shi, Y. Caspase activation, inhibition, and reactivation: a mechanistic view. Protein Sci., 2004, 13(8), 1979-1987.
[http://dx.doi.org/10.1110/ps.04789804] [PMID: 15273300]
[21]
Lai, H.; Zhao, Z.; Li, L.; Zheng, W.; Chen, T. Antiangiogenic ruthenium(ii) benzimidazole complexes, structure-based activation of distinct signaling pathways. Metallomics, 2015, 7(3), 439-447.
[http://dx.doi.org/10.1039/C4MT00312H] [PMID: 25630534]
[22]
Riedl, S.J.; Shi, Y. Molecular mechanisms of caspase regulation during apoptosis. Nat. Rev. Mol. Cell Biol., 2004, 5(11), 897-907.
[http://dx.doi.org/10.1038/nrm1496] [PMID: 15520809]
[23]
Cattaruzza, L.; Fregona, D.; Mongiat, M.; Ronconi, L.; Fassina, A.; Colombatti, A.; Aldinucci, D. Antitumor activity of gold(III)-dithiocarbamato derivatives on prostate cancer cells and xenografts. Int. J. Cancer, 2011, 128(1), 206-215.
[http://dx.doi.org/10.1002/ijc.25311] [PMID: 20209498]
[24]
Wang, C.; Youle, R.J. The role of mitochondria in apoptosis. Annu. Rev. Genet., 2009, 43, 95-118.
[http://dx.doi.org/10.1146/annurev-genet-102108-134850] [PMID: 19659442]

Rights & Permissions Print Cite
Article Metrics
22
1
© 2024 Bentham Science Publishers | Privacy Policy