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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Research Article

The In Vitro Anticancer Activity and Potential Mechanism of Action of 1-[(1R,2S)-2-fluorocyclopropyl]Ciprofloxacin-(4-methyl/phenyl/benzyl-3- aryl)-1,2,4-triazole-5(4H)-thione Hybrids

Author(s): Ya-Zhou Zhang, Hai-Lin Liu, Qian-Song He* and Zhi Xu*

Volume 20, Issue 16, 2020

Page: [1493 - 1498] Pages: 6

DOI: 10.2174/1568026620666200310123723

Price: $65

Abstract

Aim: Development of 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)- thione hybrids as potential dual-acting mechanism anticancer agent to overcome the drug resistance.

Background: Chemotherapy is an essential tool for the treatment of lung and female breast cancers, and numerous anticancer agents have been launched for this purpose. However, the clinical outcomes of chemotherapy are usually far from satisfactory due to the side effects and resistance to chemotherapeutic drugs. Thus, it is urgent to develop novel anti-lung and anti-breast cancer agents.

Objective: The primary objective of this study was to evaluate the potential of bis-isatin scaffolds with alkyl/ether linkers between the two isatin moieties against different human breast cancer cell lines including A549, MCF-7 and their drug-resistant counterparts A549/CDDP, MCF-7/ADM cells.

Methods: The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-(4-methyl/phenyl/benzyl-3-aryl)-1,2,4- triazole-5(4H)-thione hybrids were screened for their in vitro activity against drug-sensitive lung (A549), breast (MCF-7) and their drug-resistant counterparts A549/CDDP (cisplatin-resistant), MCF- 7/ADM (doxorubicin-resistant) cancer cell lines by MTT assay. The inhibitory activity of these hybrids against topoisomerase II and EGFR was also evaluated to investigate the potential mechanism of action of these hybrids.

Results: The most prominent hybrid 7k (IC50: 37.28-49.05 µM) was comparable to Vorinostat against A549 and A549/CDDP lung cancer cells, and was 2.79-2.94 times more active than Vorinostat against MCF-7 and MCF-7/ADM breast cancer cell lines. Moreover, hybrid 7k (IC50: 8.6 and 16.4 µM) also demonstrated dual inhibition against topoisomerase II and EGFR.

Conclusion: The 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin-1,2,4-triazole-5(4H)-thione hybrids possess equally activity against both drug-sensitive cancer cells and their drug-resistant counterparts, and the majority of them were no inferior to the reference Vorinostat. The mechanistic study revealed that these hybrids could inhibit both topoisomerase II and EGFR, so these hybrids can be developed as dual-acting mechanism anticancer agents.

Keywords: Fluoroquinolone, 1-[(1R, 2S)-2-fluorocyclopropyl]ciprofloxacin, 1, 2, 4-triazole-5(4H)-thione, Anticancer, Drugresistant, Mechanism.

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[1]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2020. CA Cancer J. Clin., 2020, 70(1), 7-30.
[http://dx.doi.org/10.3322/caac.21590] [PMID: 31912902]
[2]
Zaidi, S.A.; Shahzad, F.; Batool, S. Progress in cancer biomarkers monitoring strategies using graphene modified support materials. Talanta, 2020, 210, 120669
[http://dx.doi.org/10.1016/j.talanta.2019.120669] [PMID: 31987212]
[3]
International Agency for Research on Cancer. Latest global cancer data: Cancer burden rises to 18.1 million new cases and 9.6 million cancer deaths in 2018. Available from:. https://www.iarc.fr/featured-news/latest-global-cancer-data-cancer-burden-rises-to-18-1-million-new-cases-and-9-6-million-cancer-deaths-in-2018/ (Accessed 2019).
[4]
International Agency for Research on Cancer. Cancer Tomorrow. Estimated number of incident cases from 2018 to 2040, all cancers, both sexes, all ages. Available from:. https://gco.iarc.fr/tomorrow/graphic-isotype?type=0&population=900&mode=population&sex=0&cancer=39&age_group=value&apc_male=0&apc_female=0 (Accessed 2019).
[5]
Rojas, C.; Casablanca, Y. Chemotherapy, biologic, and immunotherapy breakthroughs in cancer care. Obstet. Gynecol. Clin. North Am., 2019, 46(1), 137-154.
[http://dx.doi.org/10.1016/j.ogc.2018.09.009] [PMID: 30683260]
[6]
Macchini, M.; Chiaravalli, M.; Zanon, S.; Peretti, U.; Mazza, E.; Gianni, L.; Reni, M. Chemotherapy in elderly patients with pancreatic cancer: Efficacy, feasibility and future perspectives. Cancer Treat. Rev., 2019, 72, 1-6.
[http://dx.doi.org/10.1016/j.ctrv.2018.10.013] [PMID: 30414985]
[7]
Qin, S.Y.; Cheng, Y.J.; Lei, Q.; Zhang, A.Q.; Zhang, X.Z. Combinational strategy for high-performance cancer chemotherapy. Biomaterials, 2018, 171, 178-197.
[http://dx.doi.org/10.1016/j.biomaterials.2018.04.027] [PMID: 29698868]
[8]
Chatterjee, N.; Bivona, T.G. Polytherapy and targeted cancer drug resistance. Trends Cancer, 2019, 5(3), 170-182.
[http://dx.doi.org/10.1016/j.trecan.2019.02.003] [PMID: 30898264]
[9]
Gao, F.; Wang, P.; Yang, H.; Miao, Q.; Ma, L.; Lu, G. Recent developments of quinolone-based derivatives and their activities against Escherichia coli. Eur. J. Med. Chem., 2018, 157, 1223-1248.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.095] [PMID: 30193220]
[10]
Gao, C.; Fan, Y.L.; Zhao, F.; Ren, Q.C.; Wu, X.; Chang, L.; Gao, F. Quinolone derivatives and their activities against methicillin-resistant Staphylococcus aureus (MRSA). Eur. J. Med. Chem., 2018, 157, 1081-1095.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.061] [PMID: 30179746]
[11]
Zhang, G.F.; Zhang, S.; Pan, B.; Liu, X.; Feng, L.S. 4-Quinolone derivatives and their activities against Gram positive pathogens. Eur. J. Med. Chem., 2018, 143, 710-723.
[http://dx.doi.org/10.1016/j.ejmech.2017.11.082] [PMID: 29220792]
[12]
Suaifan, G.A.R.Y.; Mohammed, A.A.M. Fluoroquinolones structural and medicinal developments (2013-2018): Where are we now? Bioorg. Med. Chem., 2019, 27(14), 3005-3060.
[http://dx.doi.org/10.1016/j.bmc.2019.05.038] [PMID: 31182257]
[13]
Gao, F.; Zhang, X.; Wang, T.; Xiao, J. Quinolone hybrids and their anti-cancer activities: An overview. Eur. J. Med. Chem., 2019, 165, 59-79.
[http://dx.doi.org/10.1016/j.ejmech.2019.01.017] [PMID: 30660827]
[14]
Dhiman, P.; Arora, N.; Thanikachalam, P.V.; Monga, V. Recent advances in the synthetic and medicinal perspective of quinolones: A review. Bioorg. Chem., 2019, 92, 103291
[http://dx.doi.org/10.1016/j.bioorg.2019.103291] [PMID: 31561107]
[15]
Jia, X.D.; Wang, S.; Wang, M.H.; Liu, M.L.; Xia, G.M.; Liu, X.J.; Chai, Y.; He, H.W. Synthesis and in vitro antitumor activity of novel naphthyridinone derivatives. Chin. Chem. Lett., 2017, 28, 235-239.
[http://dx.doi.org/10.1016/j.cclet.2016.07.024]
[16]
El-Sherief, H.A.M.; Youssif, B.G.M.; Abbas Bukhari, S.N.; Abdelazeem, A.H.; Abdel-Aziz, M.; Abdel-Rahman, H.M. Synthesis, anticancer activity and molecular modeling studies of 1,2,4-triazole derivatives as EGFR inhibitors. Eur. J. Med. Chem., 2018, 156, 774-789.
[http://dx.doi.org/10.1016/j.ejmech.2018.07.024] [PMID: 30055463]
[17]
El-Nezhawy, A.O.H.; Eweas, A.F.; Radwan, M.A.A.; El-Naggar, T.B.A. Synthesis and molecular docking studies of novel 2-phenyl-4-substituted oxazole derivatives as potential anti-cancer agents. J. Heterocycl. Chem., 2016, 53, 271-279.
[http://dx.doi.org/10.1002/jhet.2422]
[18]
Mishra, C.B.; Mongre, R.K.; Kumari, S.; Jeong, D.K.; Tiwari, M. Novel triazole-piperazine hybrid molecules induce apoptosis via activation of the mitochondrial pathway and exhibit antitumor efficacy in Osteosarcoma Xenograft nude mice model. ACS Chem. Biol., 2017, 12(3), 753-768.
[http://dx.doi.org/10.1021/acschembio.6b01007] [PMID: 28084722]
[19]
Parlak, A.E.; Tekin, S.; Karatepe, A.; Koparir, P.; Telceken, H.; Ceribası, A.O.; Karatepe, M. In vitro and histological investigation of antitumor effect of some triazole compounds in colon cancer cell line. J. Cell. Biochem., 2019, 120, e11809
[http://dx.doi.org/10.1002/jcb.28460] [PMID: 30770576]
[20]
Plech, T.; Kaproń, B.; Paneth, A.; Kosikowska, U.; Malm, A.; Strzelczyk, A.; Stączek, P.; Świątek, Ł.; Rajtar, B.; Polz-Dacewicz, M. Search for factors affecting antibacterial activity and toxicity of 1,2,4-triazole-ciprofloxacin hybrids. Eur. J. Med. Chem., 2015, 97, 94-103.
[http://dx.doi.org/10.1016/j.ejmech.2015.04.058] [PMID: 25951434]
[21]
Plech, T.; Wujec, M.; Kosikowska, U.; Malm, A.; Rajtar, B.; Polz-Dacewicz, M. Synthesis and in vitro activity of 1,2,4-triazole-ciprofloxacin hybrids against drug-susceptible and drug-resistant bacteria. Eur. J. Med. Chem., 2013, 60, 128-134.
[http://dx.doi.org/10.1016/j.ejmech.2012.11.040] [PMID: 23287058]
[22]
Hussain, S.; Ullah, F.; Sadiq, A.; Ayaz, M.; Shah, A.A.; Ali Shah, S.A.; Shah, S.M.; Nadhman, A.; Ullah, F.; Wadood, A.; El-Shazly, M. Shah, S. A. A.; Shah, S. M.; Nadhman, A.; Ullah, F.; Wadood, A.; El-Shazly, M. Cytotoxicity of Anchusa arvensis against HepG-2 cell lines: Mechanistic and computational approaches. Curr. Top. Med. Chem., 2019, 19(30), 2805-2813.
[http://dx.doi.org/10.2174/1568026619666191105103801] [PMID: 31702502]
[23]
Montealegre-Sánchez, L.; Gimenes, S.N.C.; Lopes, D.S.; Teixeira, S.C.; Solano-Redondo, L.; de Melo Rodrigues, V.; Jiménez-Charris, E. Antitumoral potential of Lansbermin-I, a novel disintegrin from porthidium lansbergii lansbergii venom on breast cancer cells. Curr. Top. Med. Chem., 2019, 19(22), 2069-2078.
[http://dx.doi.org/10.2174/1568026619666190806151401] [PMID: 31385773]

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