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

Antiproliferative Properties of 7,8-Ethylene Diamine Chelator-Lipophilic Fluoroquinolone Derivatives Against Colorectal Cancer Cell Lines

Author(s): Sara Khaleel, Yusuf Al-Hiari, Violet Kasabri*, Randa Haddadin, Rabab Albashiti, Muhammad Al-Zweri and Yasser Bustanji

Volume 22, Issue 5, 2022

Published on: 03 January, 2022

Page: [1012 - 1028] Pages: 17

DOI: 10.2174/1871520621666210623111744

Price: $65

Abstract

Background: Cancer is one of the most overwhelming diseases nowadays. It is considered the second cause of death after cardiovascular diseases. Due to the diversity of its types, stages and genetic origin, there is no available drug to treat all cancers. Serious side effects and resistance of existing drugs are other problems in the struggle against cancer. In such quest, fluoroquinolones (FQs) promising as antiproliferative compounds due to safety, low cost and lack of resistance.

Objectives: Therefore, this work aims at developing lipophilic FQs and screening their antiproliferative activity against colorectal cancer.

Methods: Nine prepared FQs were investigated for antiproliferative activity utilizing in vitro SRB method. In comparison to the antiproliferative agent cisplatin; the assessment of antiproliferative activities of these novel FQs in a panel of Colorectal Cancer Cell (CRC) lines (HT29, HCT116, SW620, CACO2, SW480) and normal periodontal ligament fibroblasts for safety examination was performed. Antibacterial activity (MIC) was conducted against Staphylococcus aureus and Escherichia coli standard strains using the broth double dilution method. Antioxidant properties were suspected as the mechanism of antiproliferative activity; thus, a DPPH test was performed to analyze radical scavenging potency of FQs compared to ascorbic acid as reference agent. FQs compounds 3-5(a-c) were prepared, characterized and their structure was confirmed using spectroscopy techniques.

Results: All compounds manifested good to excellent antiproliferative activity on HT29, HCT116, and SW620 with high safety index. The reduced series 4a, 4b and 4c exerted excellent micro to nano -molar antiproliferative activities on HT29, HCT116, and SW620 which were stronger than the reference cisplatin against all cells. The reduced group of compounds 4(a-c) revealed higher potency vs. both nitro and triazolo groups. On cell lines HT29, HCT116, and SW620, reduced 4a with 7,8-ethylene diamine,the substitution revealed the highest antiproliferative efficacy (IC50 value) approaching nano molar affinity with higher safety vs. cisplatin. The most active compound, 4a, exhibited significant potency against HCT116, and SW620 with IC50 0.6 and 0.16 μM respectively. Novel FQs (4a, 4b and 4c) also showed strong radical scavenging activity with IC50 values (μM) 0.06, 23, and 7.99, respectively. Exquisitely 4a revealed a similar pattern of activity to doxorubicin, indicating a similar mechanism of action. Strong antiproliferative and weak antibacterial activities of series 4 endorse that their mechanism involves eukaryotic topoisomerase II inhibition. This work has revealed novel FQs with excellent anticancer activity against 5 colorectal cancer (HT29, HCT116, SW620, CACO2, SW480) cell lines with a potential chelation mechanism due to 7,8-ethylene diamine chelator bridge.

Conclusion: The new FQs have confirmed that more lipophilic compounds could be more active as hypothesized. The p-halogenated aniline, N1-Butyl group in addition to 3-COOH, 8-NH2 are all essential requirements for strong antiproliferative FQ of our FQ scaffold. This work emphasizes the role of C-8 amino as part of ethylene diamine group as an essential requirement for antiproliferative FQs for the first time in the literature, entailing its role toward potential antineoplastic FQs.

Keywords: Quinolones, fluoroquinolones, triazoloquinolones, sulphorodhamine B, cisplatin, colorectal cancer.

Next »
Graphical Abstract

[1]
American Cancer Society. Cancer Facts; Treatment and Support: Atlanta, 2015.
[2]
Siegl, R.; Miller, K.; Jemal, A. Cancer Facts & Figures., 2017.
[3]
Jordan Ministry of Health, (JMoH). Cancer Incidence in Jordan; Non-communicable diseases directorate, Jordan cancer registry,. 2012.
[4]
Mortality data in Jordan 2009.Available from: . http://apps.moh.gov.jo/MOH/En/publications.php [Accessed on Jan 5th, 2021]
[5]
(a)Wu, X.Z. A new classification system of anticancer drugs - based on cell biological mechanisms. Med. Hypotheses, 2006, 66(5), 883-887.
[http://dx.doi.org/10.1016/j.mehy.2005.11.036] [PMID: 16414204]
(b)Singh, P.; Ngcoya, N.; Kumar, V. A review of the recent developments in synthetic antibreast cancer agents. Anticancer. Agents Med. Chem., 2016, 16(6), 668-685.
[http://dx.doi.org/10.2174/1871520616666151120122120] [PMID: 26584726]
[6]
(a)Bisacchi, G.S.; Hale, M.R.A. “double-edged” scaffold: Antitumor power within the antibacterial quinolone. Curr. Med. Chem., 2016, 23(6), 520-577.
[http://dx.doi.org/10.2174/0929867323666151223095839] [PMID: 26695512]
(b)Sharma, P.C.; Goyal, R.; Sharma, A.; Sharma, D.; Saini, N.; Rajak, H.; Sharma, S.; Thakur, V.K. Insights on fluoroquinolones in cancer therapy: Chemistry and recent developments. Materials Today Chem, 2020, 17, 100296.
[http://dx.doi.org/10.1016/j.mtchem.2020.100296]
(c)Asif, M. A review on anticancer and antimicrobial activity of tetrafluoroquinolone compounds. Ann. Med. Chem. Res., 2014, 1(1), 1003.
[7]
(a)Shen, L.L.; Baranowski, J.; Pernet, A.G. Mechanism of inhibition of DNA gyrase by quinolone antibacterials: specificity and cooperativity of drug binding to DNA. Biochemistry, 1989, 28(3), 85-879.
(b)Drlica, K. Mechanism of fluoroquinolone action. Curr. Opin. Microbiol., 1999, 21(7), 8-504.
[8]
Eweas, A.F.; Khalifa, N.M.; Ismail, N.S.; Al-Omar, M.A.; Soliman, A.M. Synthesis, molecular docking of novel 1,8-naphthyridine derivatives and their cytotoxic activity against HepG2 cell lines. Med. Chem. Res., 2014, 23, 76-86.
[http://dx.doi.org/10.1007/s00044-013-0604-6]
[9]
(a)Hotinski, A.K.; Lewis, I.D.; Ross, D.M. Vosaroxin is a novel topoisomerase-II inhibitor with efficacy in relapsed and refractory acute myeloid leukaemia. Expert Opin. Pharmacother., 2015, 16(9), 1395-1402.
[http://dx.doi.org/10.1517/14656566.2015.1044437] [PMID: 25958926]
(b)Abbas, J.A.; Stuart, R.K. Vosaroxin: A novel antineoplastic quinolone. Expert Opin. Investig. Drugs, 2012, 21(8), 1223-1233.
[http://dx.doi.org/10.1517/13543784.2012.699038] [PMID: 22724917]
[10]
(a)Yadav, V.; Talwar, P. Repositioning of fluoroquinolones from antibiotic to anti-cancer agents: An underestimated truth. Biomed. Pharmacother., 2019, 111, 934-946.
[http://dx.doi.org/10.1016/j.biopha.2018.12.119] [PMID: 30841473]
(b)Beberok, A.; Wrześniok, D.; Rok, J.; Rzepka, Z.; Respondek, M.; Buszman, E. Ciprofloxacin triggers the apoptosis of human triple-negative breast cancer MDA-MB-231 cells via the p53/Bax/Bcl-2 signaling pathway. Int. J. Oncol., 2018, 52(5), 1727-1737.
[http://dx.doi.org/10.3892/ijo.2018.4310] [PMID: 29532860]
(c)Yadav, V.; Varshney, P.; Sultana, S.; Yadav, J.; Saini, N. Moxifloxacin and ciprofloxacin induces S-phase arrest and augments apoptotic effects of cisplatin in human pancreatic cancer cells via ERK activation. BMC Cancer,, 2015, 15, ID 581.
[http://dx.doi.org/10.1186/s12885-015-1560-y]
(d)Seo, Kw.; Holt, R.; Jung, Y-S.; Rodriguez, C.O., Jr; Chen, X.; Rebhun, R.B. Fluoroquinolone-mediated inhibition of cell growth, S-G2/M cell cycle arrest, and apoptosis in canine osteosarcoma cell lines. PLoS One, 2012, 7(8), e42960.
[http://dx.doi.org/10.1371/journal.pone.0042960] [PMID: 22927942]
(e)Alaaeldin, R.; Nazmy, M.H.; Abdel-Aziz, M.; Abuo-Rahma, G.E.A.; Fathy, M. Cell Cycle Arrest and Apoptotic Effect of 7-(4-(N-substituted carbamoylmethyl) piperazin-1-yl) Ciprofloxacin-derivative on HCT 116 and A549 Cancer Cells. Anticancer Res., 2020, 40(5), 2739-2749.
[http://dx.doi.org/10.21873/anticanres.14245] [PMID: 32366419]
(f)Herold, C.; Ocker, M.; Ganslmayer, M.; Gerauer, H.; Hahn, E.G.; Schuppan, D. Ciprofloxacin induces apoptosis and inhibits proliferation of human colorectal carcinoma cells. Br. J. Cancer, 2002, 86(3), 443-448.
[http://dx.doi.org/10.1038/sj.bjc.6600079] [PMID: 11875713]
(g)Kan, J.Y.; Hsu, Y.L.; Chen, Y.H.; Chen, T.C.; Wang, J.Y.; Kuo, P.L. Gemifloxacin, a fluoroquinolone antimicrobial drug, inhibits migration and invasion of human colon cancer cells. BioMed Res Int., 2013.
[11]
(a)Arabiyat, S.; Kasabri, V.; Al-Hiari, Y.; Bustanji, Y.K.; Albashiti, R.; Almasri, I.M.; Sabbah, D.A. Antilipase and antiproliferative activities of novel fluoroquinolones and triazolofluoroquinolones. Chem. Biol. Drug Des., 2017, 90(6), 1282-1294.
[http://dx.doi.org/10.1111/cbdd.13049] [PMID: 28639358]
(b)Alabsi, Y.; Al-Hiari, Y.; Kasabri, V.; Arabiyat, S.; Bashiti, R.; Alalawi, S.; Al-Shahrabi, R. In vitro modulation of pancreatic lipase and proliferation of obesity related-colorectal cancer cell line panel by novel synthetic fluoroquinolones. Rev. Roum. Chim., 2018, 63(12), 1123-1134.
[12]
(a)Vichai, V.; Kirtikara, K. Sulforhodamine B colorimetric assay for cytotoxicity screening. Nat. Protoc., 2006, 1(3), 1112-1116.
[http://dx.doi.org/10.1038/nprot.2006.179] [PMID: 17406391]
(b)Papazisis, K.T.; Geromichalos, G.D.; Dimitriadis, K.A.; Kortsaris, A.H. Optimization of the sulforhodamine B colorimetric assay. J. Immunol. Methods, 1997, 208(2), 151-158.
[http://dx.doi.org/10.1016/S0022-1759(97)00137-3] [PMID: 9433470]
[13]
(a)Kasabri, V.; Afifi, F.U.; Abu-Dahab, R.; Mhaidat, N.; Bustanji, Y.K.; Abaza, I.F.; Mashallah, S. In vitro modulation of metabolic syndrome enzymes and proliferation of obesity related-colorectal cancer cell line panel by Salvia species from Jordan. Rev. Roum. Chim., 2014, 59, 693-705.
(b)El-Hamoly, T.; El-Sharawy, D.M.; El Refaye, M.S.; Abd El-Rahman, S.S. L-thyroxine modifies nephrotoxicity by regulating the apoptotic pathway: The possible role of CD38/ADP-ribosyl cyclase-mediated calcium mobilization. PLoS One, 2017, 12(9), e0184157.
[http://dx.doi.org/10.1371/journal.pone.0184157] [PMID: 28892514]
(c)AlKhalil, M.; Al-Hiari, Y.; Kasabri, V.; Arabiyat, S.; Al-Zweiri, M.; Mamdooh, N.; Telfah, A. Selected pharmacotherapy agents as antiproliferative and anti-inflammatory compounds. Drug Dev. Res., 2020, 81(4), 470-490.
[http://dx.doi.org/10.1002/ddr.21640] [PMID: 31943302]
(d)Mamdooh, N.; Kasabri, V.; Al-Hiari, Y.; Almasri, I.; Al-Alawi, S.; Bustanji, Y. Evaluation of selected commercial pharmacotherapeutic drugs as potential pancreatic lipase inhibitors and antiproliferative compounds. Drug Dev. Res., 2019, 80(3), 310-324.
[http://dx.doi.org/10.1002/ddr.21499] [PMID: 30511444]
[14]
Hoffmann, H.H.; Kunz, A.; Simon, V.A.; Palese, P.; Shaw, M.L. Broad-spectrum antiviral that interferes with de novo pyrimidine biosynthesis. Proc. Natl. Acad. Sci. USA, 2011, 108(14), 5777-5782.
[http://dx.doi.org/10.1073/pnas.1101143108] [PMID: 21436031]
[15]
Mishra, K.; Ojha, H.; Chaudhury, N.K. Estimation of antiradical properties of antioxidants using DPPH assay: A critical review and results. Food Chem., 2012, 130(4), 1036-1043.
[http://dx.doi.org/10.1016/j.foodchem.2011.07.127]
[16]
(a)Marinova, G.; Batchvarov, V. Evaluation of the methods for determination of the free radical scavenging activity by DPPH. Bulg. J. Agric. Sci., 2011, 17(1), 11-24.
(b)Haida, Z.; Hakiman, M. A comprehensive review on the determination of enzymatic assay and nonenzymatic antioxidant activities. Food Sci. Nutr., 2019, 7(5), 1555-1563.
[http://dx.doi.org/10.1002/fsn3.1012] [PMID: 31139368]
(c)Hidayat, M.A.; Fitri, A.; Kuswandi, B. Scanometry as microplate reader for high throughput method based on DPPH dry reagent for antioxidant assay. Acta Pharm. Sinica B, 2017, 7(3), 395-400.
[http://dx.doi.org/10.1016/j.apsb.2017.02.001]
(d)Karahan, F.; Kulak, M.; Urlu, E.; Gözüacik, H.G.; Böyümez, T.; Şekeroğlu, N.; Doganturk, I.H. Total phenolic content, ferric reducing and DPPH scavenging activity of Arum dioscoridis. Nat. Prod. Res., 2015, 29(17), 1678-1683.
[http://dx.doi.org/10.1080/14786419.2014.991320] [PMID: 25520041]
(e)Paulpriya, K.; Lincy, M.P.; Tresina, P.S.; Mohan, V.R. In vitro antioxidant activity, total phenolic and total flavonoid contents of aerial part extracts of Daphniphyllum neilgherrense (wt.) rosenth. J. Bio Innov, 2015, 4(6), 257-268.
(f)Shalaby, E.A.; Shanab, S.M.M. Antioxidant compounds, assays of determination and mode of action. Afr. J. Pharm. Pharmacol., 2013, 7(10), 528-539.
[http://dx.doi.org/10.5897/AJPP2013.3474]
(g)Sharma, O.P.; Bhat, T.K. DPPH antioxidant assay revisited. Food Chem., 2009, 113(12), 1202-1205.
[http://dx.doi.org/10.1016/j.foodchem.2008.08.008]
(h)Shen, Q.; Zhang, B.; Xu, R.; Wang, Y.; Ding, X.; Li, P. Antioxidant activity in vitro of the selenium-contained protein from the Se-enriched Bifidobacterium animalis. Anaerobe, 2010, 16(4), 380-386.
[http://dx.doi.org/10.1016/j.anaerobe.2010.06.006] [PMID: 20601030]
[17]
Clinical and Laboratory Standards Institute (CLSI). Performance standards for antimicrobial susceptibility testing; Twenty-sixth informational supplementCLSI document M100-S26; Clinical and Laboratory Standards Institute: Wayne, PA, 2016. (b) McFarland, J. The nephelometer: An instrument for estimating the number of bacteria in suspensions used for calculating the opsonic index and for vaccines. J. Am. Med. Assoc., 1907, 14, 1176-1178.
[http://dx.doi.org/10.1001/jama.1907.25320140022001f]
[18]
(a)Arabiyat, S.; Kasabri, V.; Al-Hiari, Y.; Al-Masri, I.; Alalawi, S.; Bustanji, Y. Dual glycation-inflammation modulation, DPP-IV and pancreatic lipase inhibitory potentials and antiproliferative activity of novel flouroquinolones. Asian Pac. J. Cancer Prev., 2019, 20(8), 2503-2514.
[http://dx.doi.org/10.31557/APJCP.2019.20.8.2503] [PMID: 31450926]
(b)Al-Ma’ani, A.; Al-Hiari, Y.; Kasabri, V.; Mamdooh, N.; Alalawi, S.; Telfah, A. Functionalised triazoloquinolones as a potentially novel class of antidiabesity and antiproliferative compounds: synthesis and pharmacological appraisal. Anal. Chem. Lett., 2019, 9(6), 727-746.
[http://dx.doi.org/10.1080/22297928.2019.1699857]
(c)Arabiyat, S.; Kasabri, V.; Al-Hiari, Y. Antilipolytic-antiproliferative activity of novel antidiabesity triazolo/fluoroquinolones. Jordan J. Pharm. Sci., 2020, 13(1), 85-100.
(d)Al-Hiari, Y.M.; Qandil, A.M.; Al-Zoubi, R.M. Al- Zweiri, M.H.; Darwish, R.M.; Shattat, G.F.; Al-Qirim, T.M. Synthesis and antibacterial activity of novel 7-haloanilino-8-nitrofluoroquinolone derivatives. Med. Chem. Res., 2011, 12(10), 200-250.

Rights & Permissions Print Cite
Article Metrics
20
1
© 2024 Bentham Science Publishers | Privacy Policy