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Anti-Cancer Agents in Medicinal Chemistry

Author(s): Gulsen A. Çiftçi*, Halide E. Temel and Leyla Yurttaş

DOI: 10.2174/1871520621666210708095110

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Apoptotic Effect of Novel Benzimidazole Derivatives Bearing Pyridyl/Pyrimidinyl Piperazine Moiety

Page: [1780 - 1792] Pages: 13

  • * (Excluding Mailing and Handling)

Abstract

Background: Benzimidazole derivatives bearing pyridyl/pyrimidinyl piperazine moiety has attracted attention in medicinal chemistry and modern drug discovery since it exhibited a variety of biological activities, including anticancer activity.

Objective: In this study, we designed and synthesized novel 1-[2-oxo-2-(4-substituted phenyl)ethyl]benzimidazol-2- yl)methyl 4-(2-pyridyl/pyrimidin-2-yl)piperazine-1-carbodithioate derivatives (2a-m). We also investigated their anticancer activities against A549 lung adenocarcinoma and C6 rat glioma cell lines. We further studied the selectivity of the compounds against the NIH/3T3 mouse embryonic fibroblast cell line. Cholinesterase inhibition effects of these compounds were also investigated to measure the relationship between anticancer activity and cholinesterases.

Methods: The cytotoxic activities of these acquired thirteen final compounds were screened using MTT assay on A549, C6, and NIH/3T3 cell lines. Cell proliferation ELISA, BRDU (colorimetric) assay was used to measure the proliferation in replicative cells in which DNA synthesis occurs. Flow cytometric analysis was used to measure apoptotic cell percentages, caspase 3 activity, and mitochondrial membrane depolarised cell percentages.

Results: Compounds 2e, 2f, and 2k were shown to be the most active antitumor agents with selective cytotoxicities (the results for A549 were 76.58±6.43, 55.13±5.75, and 32.94±3.02 μM, respectively; and for C6 they were 86.48±3.60, 97.12±30.21, and 59.29±3.95 μM, respectively), high DNA synthesis inhibition rates and high apoptotic cell percentages on both cell lines.

Conclusion: The results showed that compounds 2e, 2f, and 2k have potential anticancer activity against A549 and C6 cell lines.

Keywords: Anticancer, apoptosis, benzimidazoles, A549 and C6 glioma, modulators, anticancer activity.

Graphical Abstract

[1]
Abdel-Ghaffar, N.F. Synthesis, reactions, structure-activity rela-tionship of 2-benzimidazole analogs as anticancer agents and study their molecular docking. Pharma Chem., 2013, 5(5), 243-257.
[2]
Refaat, H.M. Synthesis and anticancer activity of some novel 2-substituted benzimidazole derivatives. Eur. J. Med. Chem., 2010, 45(7), 2949-2956.
[http://dx.doi.org/10.1016/j.ejmech.2010.03.022] [PMID: 20399544]
[3]
Bansal, Y.; Silakari, O. The therapeutic journey of benzimidazoles: A review. Bioorg. Med. Chem., 2012, 20(21), 6208-6236.
[http://dx.doi.org/10.1016/j.bmc.2012.09.013] [PMID: 23031649]
[4]
Gaba, M.; Singh, S.; Mohan, C. Benzimidazole: An emerging scaffold for analgesic and anti-inflammatory agents. Eur. J. Med. Chem., 2014, 76, 494-505.
[http://dx.doi.org/10.1016/j.ejmech.2014.01.030] [PMID: 24602792]
[5]
Abu-Bakr, S.M.; Bassyouni, F.A.; Rehim, M.A. Pharmacological evaluation of benzimidazole derivatives with potential antiviral and antitumor activity. Res. Chem. Intermed., 2012, 38, 2523-2545.
[http://dx.doi.org/10.1007/s11164-012-0569-y]
[6]
Yadav, G.; Ganguly, S. Structure activity relationship (SAR) study of benzimidazole scaffold for different biological activities: A mini-review. Eur. J. Med. Chem., 2015, 97, 419-443.
[http://dx.doi.org/10.1016/j.ejmech.2014.11.053] [PMID: 25479684]
[7]
Narasimhan, B.; Sharma, D.; Kumar, P. Benzimidazole: A medici-nally important heterocyclic moiety. Med. Chem. Res., 2012, 21, 269-283.
[http://dx.doi.org/10.1007/s00044-010-9533-9]
[8]
Khokra, S.L.; Choudhary, D. Benzimidazole an important scaffold in drug discovery. Asi. J. Biochem. Pharm. Res., 2011, 1(3), 476-486.
[9]
El Rashedy, A.A.; Aboul-Enein, H.Y. Benzimidazole derivatives as potential chemotherapeutic agents. Curr. Drug Ther., 2013, 8, 1-14.
[http://dx.doi.org/10.2174/1574885511308010001]
[10]
Husain, A.; Varshney, M.M.; Rashid, M.; Mishra, R.; Akhter, A. Benzimidazole: A valuable insight into the recent advances and bi-ological activities. J. Pharm. Res., 2011, 4(2), 413-419.
[11]
Sivakumar, R.; Pradeepchandran, R.; Jayaveera, K.N.; Kumarnalla-sivan, P.; Vijaianand, P.R.; Venkatnarayanan, R. Benzimidazole: An attractive pharmacophore in medicinal chemistry. Int. J. Pharm. Res., 2011, 3(3), 19-31.
[12]
Jenny, V.D.; Rashmi, S.C.; Nileshwari, S.C.; Patil, S.T. A short review on chemistry and potential activities of benzimidazole mol-ecule. IJPT, 2013, 5, 2477-2494.
[13]
Kale, M.; Suradkar, C. Benzimidazole: An important biological heterocyclic scaffold. J. Curr. Pharm. Res., 2014, 4(2), 1159-1167.
[http://dx.doi.org/10.33786/JCPR.2014.v04i02.008]
[14]
Santosh, P.C.; Pandeya, S.N.; Pathak, A.K. Benzimidazole: A versatile chemical entity. Int. J. Ayurveda Pharm., 2011, 2, 1726-1737.
[15]
Hu, L.; Kully, M.L.; Boykin, D.W.; Abood, N. Synthesis and in vitro activity of dicationic bis-benzimidazoles as a new class of an-ti-MRSA and anti-VRE agents. Bioorg. Med. Chem. Lett., 2009, 19(5), 1292-1295.
[http://dx.doi.org/10.1016/j.bmcl.2009.01.075] [PMID: 19208475]
[16]
He, Y.; Yang, J.; Wu, B.; Risen, L.; Swayze, E.E. Synthesis and biological evaluations of novel benzimidazoles as potential antibac-terial agents. Bioorg. Med. Chem. Lett., 2004, 14(5), 1217-1220.
[http://dx.doi.org/10.1016/j.bmcl.2003.12.051] [PMID: 14980669]
[17]
Hu, L.; Kully, M.L.; Boykin, D.W.; Abood, N. Optimization of the central linker of dicationic bis-benzimidazole anti-MRSA and anti-VRE agents. Bioorg. Med. Chem. Lett., 2009, 19(13), 3374-3377.
[http://dx.doi.org/10.1016/j.bmcl.2009.05.061] [PMID: 19481935]
[18]
Mavrova, A.T.; Tsenov, P.D.Y.A.; Anichinaa, K.K.; Vutchev, D.I. Synthesis and antitrichinellosis activity of some bis(benzimidazol-2-yl)amines. Bioorg. Med. Chem., 2007, 15(18), 6291-6297.
[19]
Remers, W.A.; Iyengar, B.S.; Dorr, R.T.; Wisner, L.; Bates, R.B. Synthesis and antitumor activity of heterocycles related to car-bendazim. J. Heterocycl. Chem., 2015, 52, 136-141.
[http://dx.doi.org/10.1002/jhet.1976]
[20]
Abdel-Mohsen, H.T.; Ragab, F.A.F.; Ramla, M.M.; El Diwani, H.I. Novel benzimidazole-pyrimidine conjugates as potent antitumor agents. Eur. J. Med. Chem., 2010, 45(6), 2336-2344.
[http://dx.doi.org/10.1016/j.ejmech.2010.02.011] [PMID: 20356655]
[21]
Aslanian, R.; Zhu, X.; Vaccaro, H.A.; Shih, N.Y.; Piwinski, J.J.; Williams, S.M.; West, R.E. Bioorg. Med. Chem. Lett., 2008, 18(18), 5032-5036.
[http://dx.doi.org/10.1016/j.bmcl.2008.08.008] [PMID: 18752952]
[22]
Singla, P.; Luxami, V.; Paul, K. Benzimidazole-biologically attrac-tive scaffold for protein kinase inhibitors. RSC Advances, 2014, 4, 12422-12440.
[http://dx.doi.org/10.1039/c3ra46304d]
[23]
Yurttas, L.; Demirayak, S.; Ciftci, G.A. Cytotoxic, antiproliferative and apoptotic effects of new benzimidazole derivatives on A549 lung carcinoma and C6 glioma cell lines. Anticancer. Agents Med. Chem., 2015, 15(9), 1174-1184.
[http://dx.doi.org/10.2174/1871520615666150703122625] [PMID: 26138412]
[24]
Yurttaş, L.; Demirayak, Ş.; Çiftçi, G.A.; Yıldırım, S.U.; Kaplancıklı, Z.A. Synthesis and biological evaluation of some 1,2-disubstituted benzimidazole derivatives as new potential anticancer agents. Arch. Pharm. (Weinheim), 2013, 346(5), 403-414.
[http://dx.doi.org/10.1002/ardp.201200452] [PMID: 23526768]
[25]
Demirayak, S.; Abu Mohsen, U. Anticancer and anti-HIV activities of some pyrido/pyrazino-benzimidazole derivatives. Acta Pharm. Turc., 1998, 40, 9-12.
[26]
Demirayak, S.; Abu Mohsen, U.; Cağri Karaburun, A. Synthesis and anticancer and anti-HIV testing of some pyrazino[1,2-a]benzimidazole derivatives. Eur. J. Med. Chem., 2002, 37(3), 255-260.
[http://dx.doi.org/10.1016/S0223-5234(01)01313-7] [PMID: 11900869]
[27]
Demirayak, S.; Kayagil, I.; Yurttas, L. Microwave supported syn-thesis of some novel 1,3-diarylpyrazino[1,2-a]benzimidazole deriv-atives and investigation of their anticancer activities. Eur. J. Med. Chem., 2011, 46(1), 411-416.
[http://dx.doi.org/10.1016/j.ejmech.2010.11.007] [PMID: 21122952]
[28]
Demirayak, Ş.; Yurttaş, L. Synthesis and anticancer activity of some 1,2,3-trisubstituted pyrazinobenzimidazole derivatives. J. Enzyme Inhib. Med. Chem., 2014, 29(6), 811-822.
[http://dx.doi.org/10.3109/14756366.2013.858142] [PMID: 24456294]
[29]
Y. Yurttaş, L.; Ozkay, Y.; Demirci, F.; Göger, G.; Yıldırım, Ş.U.; Mohsen, A.U.; Öztürk, Ö.; Kaplancıklı, Z.A. Synthesis, antican-didal activity, and cytotoxicity of some thiazole derivatives with di-thiocarbamate side chains. Turk. J. Chem., 2014, 38, 815-824.
[http://dx.doi.org/10.3906/kim-1312-62]
[30]
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]
[31]
Yurttaş, L.; Çavuşoğlu, B.K.; Çiftçi, G.A.; Temel, H.E. Synthesis and biological evaluation of new 1,3,4-oxadiazoles as potential an-ticancer agents and enzyme inhibitors. Anticancer. Agents Med. Chem., 2018, 18(6), 914-921.
[http://dx.doi.org/10.2174/1871520618666180322123327] [PMID: 29577865]
[32]
Malíková, J.; Swaczynová, J.; Kolár, Z.; Strnad, M. Anticancer and antiproliferative activity of natural brassinosteroids. Phytochemistry, 2008, 69(2), 418-426.
[http://dx.doi.org/10.1016/j.phytochem.2007.07.028] [PMID: 17869317]
[33]
Desai, J.V.; Chavan Rashmi, S.; Chaudhari Nileshwari, S.; Patil, S.T. A short review on chemistry and potential activities of ben-zimidazole molecule. Int. J. Pharm. Technol., 2013, 5, 2477-2494.
[34]
Ng, R.A.; Guan, J.; Alford, V.C., Jr; Lanter, J.C.; Allan, G.F.; Sbriscia, T.; Lundeen, S.G.; Sui, Z. 2-(2,2,2-Trifluoroethyl)-5,6-dichlorobenzimidazole derivatives as potent androgen receptor an-tagonists. Bioorg. Med. Chem. Lett., 2007, 17(4), 955-958.
[http://dx.doi.org/10.1016/j.bmcl.2006.11.047] [PMID: 17134895]
[35]
Guo, J.; Feng, Z.; Huang, Z.; Wang, H.; Lu, W. MicroRNA-217 functions as a tumour suppressor gene and correlates with cell re-sistance to cisplatin in lung cancer. Mol. Cells, 2014, 37(9), 664-671.
[http://dx.doi.org/10.14348/molcells.2014.0121] [PMID: 25234467]
[36]
Noda, S.; Yoshimura, S.; Sawada, M.; Naganawa, T.; Iwama, T.; Nakashima, S.; Sakai, N. Role of ceramide during cisplatin-induced apoptosis in C6 glioma cells. J. Neurooncol., 2001, 52(1), 11-21.
[http://dx.doi.org/10.1023/A:1010624823158] [PMID: 11451199]
[37]
Atmaca, H.; İlhan, S.; Batır, M.B.; Pulat, Ç.Ç.; Güner, A.; Bektaş, H. Novel benzimidazole derivatives: Synthesis, in vitro cytotoxici-ty, apoptosis and cell cycle studies. Chem. Biol. Interact., 2020, 327(327)109163
[http://dx.doi.org/10.1016/j.cbi.2020.109163] [PMID: 32534988]
[38]
Dettmann, S.; Szymanowitz, K.; Wellner, A.; Schiedel, A.; Müller, C.E.; Gust, R. 2-phenyl-1-[4-(2-piperidine-1-yl-ethoxy)benzyl]-1H-benzimidazoles as ligands for the estrogen receptor: Synthesis and pharmacological evaluation. Bioorg. Med. Chem., 2010, 18(14), 4905-4916.
[http://dx.doi.org/10.1016/j.bmc.2010.06.016] [PMID: 20598555]
[39]
Azam, M.; Khan, A.A.; Al-Resayes, S.I.; Islam, M.S.; Saxena, A.K.; Dwivedi, S.; Musarrat, J.; Trzesowska-Kruszynska, A.; Kruszynski, R. Synthesis and characterization of 2-substituted ben-zimidazoles and their evaluation as anticancer agent. Spectrochim. Acta A Mol. Biomol. Spectrosc., 2015, 142, 286-291.
[http://dx.doi.org/10.1016/j.saa.2015.01.106] [PMID: 25706598]
[40]
Wang, X.; Wei, Y.; Yuan, S.; Liu, G.; Lu, Y.; Zhang, J.; Wang, W. Potential anticancer activity of tanshinone IIA against human breast cancer. Int. J. Cancer, 2005, 116(5), 799-807.
[http://dx.doi.org/10.1002/ijc.20880] [PMID: 15849732]
[41]
Fulda, S.; Debatin, K.M. Extrinsic versus intrinsic apoptosis path-ways in anticancer chemotherapy. Oncogene, 2006, 25(34), 4798-4811.
[http://dx.doi.org/10.1038/sj.onc.1209608] [PMID: 16892092]
[42]
Hickman, J.A. Apoptosis induced by anticancer drugs. Cancer Metastasis Rev., 1992, 11(2), 121-139.
[http://dx.doi.org/10.1007/BF00048059] [PMID: 1327566]
[43]
Yurttaş, L.; Ciftci, G.A.; Aksoy, M.O.; Demirayak, Ş. Novel ben-zimidazole derivatives: Cytotoxic and apoptotic properties on lung cancer cell line. Lett. Drug Des. Discov., 2020, 17(10), 1127-1236.
[http://dx.doi.org/10.2174/1570180817999200513091613]
[44]
Porter, A.G. Flipping the safety catch of procaspase-3. Nat. Chem. Biol., 2006, 2(10), 509-510.
[http://dx.doi.org/10.1038/nchembio1006-509] [PMID: 16983381]
[45]
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35(4), 495-516.
[http://dx.doi.org/10.1080/01926230701320337] [PMID: 17562483]
[46]
Hegde, M.; Kumar, K. S.S.; Thomas, E.; Ananda, H.; Sathees, C.; Raghavan, S.S.; Rangappa, K.S. A novel benzimidazole derivative binds to the DNA minor groove and induces apoptosis in leukemic cells. RSC Advances, 2015, 5, 93194-93208.
[http://dx.doi.org/10.1039/C5RA16605E]
[47]
Youssef, A.M.; Malki, A.; Badr, M.H.; Elbayaa, R.Y.; Sultan, A.S. Synthesis and anticancer activity of novel benzimidazole and ben-zothiazole derivatives against HepG2 liver cancer cells. Med. Chem., 2012, 8(2), 151-162.
[http://dx.doi.org/10.2174/157340612800493719] [PMID: 22385181]
[48]
Nayak, V.L.; Nagesh, N.; Ravikumar, A.; Bagul, C.; Vishnuvardhan, M.V.P.S.; Srinivasulu, V.; Kamal, A. 2-aryl benzimidazole conjugate induced apoptosis in human breast cancer MCF-7 cells through caspase independent pathway. Apoptosis, 2017, 22(1), 118-134.
[http://dx.doi.org/10.1007/s10495-016-1290-x] [PMID: 27770267]