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
General Research Article

In vitro Antiproliferative Properties of Lipophililic-Acid Chelating Fluoroquinolones and TriazoloFluoroquinolones with 7-dihaloanilinosubstitution

Author(s): Tasneem Hallaq, Yusuf Al-Hiari, Violet Kasabri*, Rabab AlBashiti, Sundus AlAlawi and Ahmad Telfah

Volume 22, Issue 19, 2022

Published on: 04 August, 2022

Page: [3304 - 3321] Pages: 18

DOI: 10.2174/1871520622666220513154744

Price: $65

Abstract

Background: Incidence rates and prevalence of cancer are substantially high globally. New safe therapeutic drugs are endorsed to overcome the high toxicity and poor safety profile of clinical anticancer agents.

Objective: As antineoplastic Vosaroxin is a commercial fluoroquinolone (FQ), we hypothesize that superlative antiproliferation activity of lipophilic FQs/TFQs series correlates to their acidic groups and C8-C7 ethylene diamine Chelation Bridge along with bulky dual halogenations.

Methods: We tested dual lipophilic- acidic chelating FQs with a genuine potential of antiproliferative propensities based on their dual DPPH- and NO- radicals scavenging biocapacities using cell based – and colorimetric assays vs. respective reference agents as their molecular action mechanism.

Results: In this work, 9 lipophilic-acid chelating FQs and their cyclized TriazoloFQs (TFQs) designed to bear 7- dihaloanilino substituents with a special focus on dichlorosubstitutions have been prepared, characterized and screened against breast T47D and MCF7, Pancreatic PANC1, colorectal HT29, cervical HELA, lung A375, skin A549, and Leukaemia K562 cancer cell lines using sulforhodamine B colorimetric bioassay. Parameters including potency, toxicity, and selectivity (potency/toxicity) have been reported along with DPPH- and NO- radicals’ scavenging propensities - as their molecular action mechanism- in comparison to ascorbic acid and indomethacin, respectively. Using Griess assay in lipopolysaccharide (LPS) prompted RAW264.7 macrophages inflammation, IC50 values (μM) in the ascending order of new FQs’ NO scavenging/antiinflammation capacity were 4a < 3a < 4c < indomethacin (23.8 < 33.4 < 36 vs. indomethacin’s 124, respectively). Exceptionally unlike the rest, reduced FQ, 4b exhibited remarkably superior DPPH radical scavenging capacity to ascorbic acid (IC50 values (μM) 19.9 vs. 123.9, p < 0.001). In comparison to cisplatin; nitroFQs (3a, 3b and 3c), the reduced FQs (4a, 4b, and 4c) and the TFQs (5a, 5b and 5c) exerted substantial micromolar antiproliferation IC50 values < 50 μM in cervical Hela cancer cells but lacked comparable bioactivity in leukaemia K562. In both breast MCF7 and T47D cancer cell lines, FQs/TFQs 4a < 3a < 5b (respective IC50 values (μM) 0.52 < 22.7 < 24 vs. cisplatin’s 41.8 and 0.03 < 4.8 < 27 vs. cisplatin’s 509), and in both GI system colorectal HT29 and pancreatic PANC1 cancer cells FQs/TFQs 4a < 3a < 5b and 4a< 3a (respective IC50 values (μM) 0.12 < 3.5 < 15.9 vs. cisplatin’s 148 and 1.5 < 10.4 vs. cisplatin’s 25.5), exerted nanomolar-micromolar affinities of antiproliferation potencies < 50μM. Besides in lung A375 cancer cells FQs/TFQs 4c < 4a < 3a and in skin A549 cancer cells 5c < 3c < 4a < 3a < 4c (respective IC50 values (μM) 0.07 < 3.2 < 10.3 vs. cisplatin’s 390 and 0.5 < 2.3 < 3.8 < 8.8 < 17.3 vs. cisplatin’s 107) exhibited nanomolar-micromolar antineoplastic capacities < 50 μM. Their spectrum of selectivity indices for safety in fibroblasts PDL-based 72h incubations was reported. Unequivocally 4b reduction of viability effectiveness linked with its DPPH radical scavenging effects (without a matching antiinflammation effect). Explicitly 4a, 3a and 4c exerted exquisite antiinflammation-selective cytotoxicity duality in vitro.

Conclusion: Such a new potential chelation mechanism can explain the pronounced difference in antineoplastic activity of new FQs/TFQs.

Keywords: Fluoroquinolone, halogenations, colorimetric, bioassay, spectrum, antiinflammation.

« Previous
Graphical Abstract

[1]
Chen, K.T.J.; Gilabert-Oriol, R.; Bally, M.B.; Leung, A.W.Y. Recent treatment advances and the role of nanotechnology, combination products, and immunotherapy in changing the therapeutic landscape of acute myeloid leukemia. Pharm. Res., 2019, 36(9), 125.
[http://dx.doi.org/10.1007/s11095-019-2654-z] [PMID: 31236772]
[2]
Chen, L.; Deng, H.; Cui, H.; Fang, J.; Zuo, Z.; Deng, J.; Li, Y.; Wang, X.; Zhao, L. Inflammatory responses and inflammation-associated diseases in organs. Oncotarget, 2017, 9(6), 7204-7218.
[http://dx.doi.org/10.18632/oncotarget.23208] [PMID: 29467962]
[3]
(a) American Cancer Society, Facts & Figures. 2020. Available from:. https://www.cancer.org/research/cancer-facts-statistics/allcancer- facts-figures/cancer-facts-figures-2020.html Accessed on August 2021
(b) 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]
[4]
(a) Ferlay, J.; Colombet, M.; Soerjomataram, I.; Dyba, T.; Randi, G.; Bettio, M.; Gavin, A.; Visser, O.; Bray, F. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries and 25 major cancers in 2018. Eur. J. Cancer, 2018, 103, 356-387.
[http://dx.doi.org/10.1016/j.ejca.2018.07.005] [PMID: 30100160]
(b) Ferlay, J.; Steliarova-Foucher, E.; Lortet-Tieulent, J.; Rosso, S.; Coebergh, J.W.W.; Comber, H.; Forman, D.; Bray, F. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur. J. Cancer, 2013, 49(6), 1374-1403.
[http://dx.doi.org/10.1016/j.ejca.2012.12.027] [PMID: 23485231]
[5]
Schetter, A.J.; Heegaard, N.H.; Harris, C.C. Inflammation and cancer: Interweaving microRNA, free radical, cytokine and p53 pathways. Carcinogenesis, 2010, 31(1), 37-49.
[http://dx.doi.org/10.1093/carcin/bgp272] [PMID: 19955394]
[6]
Akhdar, H.; Legendre, C.; Morel, F. Anticancer drug metabolism: Chemotherapy resistance and new therapeutic approach; Topics Drug Metabol, 2012, pp. 137-170.
[http://dx.doi.org/10.5772/30015]
[7]
Sharma, P.C.; Sharma, D.; Sharma, A.; Saini, N.; Goyal, R.; Ola, M.; Chawla, R.; Thakur, V.K. Hydrazone comprising compounds as promising anti-infective agents: Chemistry and structure-property relationship. Mater. Today Chem., 2020, 18, 100349.
[http://dx.doi.org/10.1016/j.mtchem.2020.100349]
[8]
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 FQs. Rev. Roum. Chim., 2018, 63(12), 1123-1134.
[9]
Arabiyat, S.; Kasabri, V.; Al-Hiari, Y.; Al-Masri, I.; Alalawi, S.; Bustanji, Y. Dual glycation-inflammation modulation, DPP IV and pancraetic lipase inhibitory potentials and antiproliferative activity of novel FQs. Asian Pac. J. Cancer Prev., 2019, 20(8), 2503-2514.
[http://dx.doi.org/10.31557/APJCP.2019.20.8.2503] [PMID: 31450926]
[10]
Assanga, S.B.I.; Lujan, L.M.L.; Gil-Salido, A.A.; Espinoza, C.L.L.; Angulo, D.F.; Rubio-Pino, J.L.; Riera, R.B. Antiinflammatory activity and modulate oxidative stress of bucidabuceras in lipopolysaccharide-stimulated RAW 264.7 macrophages and carrageenan-induced acute paw oedema in rats. J. Med. Plants Res., 2017, 11(12), 239-252.
[http://dx.doi.org/10.5897/JMPR2017.6334]
[11]
Ghimeray, A.K.; Lee, H.Y.; Kim, Y.H.; Ryu, E.K.; Chang, M.S. Evaluation of antioxidant and antiinflammatory Effect of Rhododendron brachycarpum extract used in skin care product by in vitro and in vivo test. Technol. Invest., 2015, 6(2), 105-111.
[http://dx.doi.org/10.4236/ti.2015.62011]
[12]
Huang, J.; Wang, Y.; Li, C.; Wang, X.; He, X. Antiinflammatory oleanolic triterpenes from Chinese acorns. Molecules, 2016, 21(5), 669-677.
[http://dx.doi.org/10.3390/molecules21050669]
[13]
Abdul Fattah, T.; Saeed, A.; Al-Hiari, Y.M.; Kasabri, V.; Almasri, I.M.; AlAlawi, S.; Larika, F.A.; Channara, P.A. Functionalized furo[3,2-c] coumarins as anti-proliferative, anti-lipolytic, and antiinflammatory compounds: Synthesis and molecular docking studies. J. Mol. Struct., 2019, 1179, 390-400.
[http://dx.doi.org/10.1016/j.molstruc.2018.11.014]
[14]
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]
[15]
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.
[16]
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]
[17]
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. Sin. B, 2017, 7(3), 395-400.
[http://dx.doi.org/10.1016/j.apsb.2017.02.001] [PMID: 28540178]
[18]
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]
[19]
Litwinienko, G.; Ingold, K.U. Abnormal solvent effects on hydrogen atom abstraction. 2. Resolution of the curcumin antioxidant controversy. The role of sequential proton loss electron transfer. J. Org. Chem., 2004, 69(18), 5888-5896.
[http://dx.doi.org/10.1021/jo049254j] [PMID: 15373474]
[20]
(a) American type tissue culture A375.S2 (ATCC® CRL-1872™), 2016.
(b) Kaur, G.; Dufour, J.M. Cell lines: Valuable tools or useless artifacts. Spermatogenesis, 2012, 2(1), 1-5.
[http://dx.doi.org/10.4161/spmg.19885] [PMID: 22553484]
[21]
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]
[22]
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]
[23]
(a) Bacchi, S.; Palumbo, P.; Sponta, A.; Coppolino, M.F. Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review. Antiinflamm. Antiallergy Agents Med. Chem., 2012, 11(1), 52-64.
[http://dx.doi.org/10.2174/187152312803476255] [PMID: 22934743]
(b) 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]
[24]
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]
[25]
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]
[26]
Hussain, S.P.; Harris, C.C. Inflammation and cancer: An ancient link with novel potentials. Int. J. Cancer, 2007, 121(11), 2373-2380.
[http://dx.doi.org/10.1002/ijc.23173] [PMID: 17893866]
[27]
Jumah, S. Antiproliferative properties of new FQs derivatives, A Masters’ Thesis, School of Pharmacy, University of Jordan, 2018.
[28]
Mitscher, L.A. Bacterial topoisomerase inhibitors: Quinolone and pyridone antibacterial agents. Chem. Rev., 2005, 105(2), 559-592.
[http://dx.doi.org/10.1021/cr030101q] [PMID: 15700957]
[29]
Al-Hiari, Y.M.; Al-Mazari, I.S.; Shakya, A.K.; Darwish, R.M.; Abu-Dahab, R. Synthesis and antibacterial properties of new 8-nitrofluoroquinolone derivatives. Molecules, 2007, 12(6), 1240-1258.
[http://dx.doi.org/10.3390/12061240] [PMID: 17876293]
[30]
(a) 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]
(b) Jamieson, G.C.; Fox, J.A.; Poi, M.; Strickland, S.A. Molecular and pharmacologic properties of the anticancer quinolone derivative Vosaroxin: A new therapeutic agent for acute myeloid leukemia. Drugs, 2016, 76(13), 1245-1255.
[http://dx.doi.org/10.1007/s40265-016-0614-z] [PMID: 27484675]
(c) 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. Mater. Today Chem., 2020, 17, 100296.
[http://dx.doi.org/10.1016/j.mtchem.2020.100296]
[31]
Bisacchi, G.S.; Hale, M.R.A.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]
[32]
Saptarini, N.M.; Herawati, I.E. Comparative antioxidant activity on the Ficus benjamina and Annona reticulata leaves. Int. J. Public Health Sci., 2015, 4(1), 6-21.
[33]
Qashou, E. Antiproliferative activity of lipophilic fluroquinolonesbased scaffold against a panel of solid and liquid cancer cell lines., A Masters’ Thesis, School of Pharmacy, University of Jordan, 2020.
[34]
Kurzwernhart, A.; Kandioller, W.; Bartel, C.; Bächler, S.; Trondl, R.; Mühlgassner, G.; Jakupec, M.A.; Arion, V.B.; Marko, D.; Keppler, B.K.; Hartinger, C.G. Targeting the DNA-topoisomerase complex in a double-strike approach with a topoisomerase inhibiting moiety and covalent DNA binder. Chem. Commun. (Camb.), 2012, 48(40), 4839-4841.
[http://dx.doi.org/10.1039/c2cc31040f] [PMID: 22498692]
[35]
(a) Angeloni, C.; Hrelia, S. Quercetin reduces inflammatory responses in LPS-stimulated cardiomyoblasts. Oxid. Med. Cell. Longev., 2012, 2012(2), 837104.
[http://dx.doi.org/10.1155/2012/837104] [PMID: 22685622]
(b) Kleemann, R.; Verschuren, L.; Morrison, M.; Zadelaar, S.; van Erk, M.J.; Wielinga, P.Y.; Kooistra, T. Anti-inflammatory, anti-proliferative and anti-atherosclerotic effects of quercetin in human in vitro and in vivo models. Atherosclerosis, 2011, 218(1), 44-52.
[http://dx.doi.org/10.1016/j.atherosclerosis.2011.04.023] [PMID: 21601209]

Rights & Permissions Print Cite
Article Metrics
34
2
© 2024 Bentham Science Publishers | Privacy Policy