Top

Published in:

01-07-2021 | Piperazine | Original Paper

Biological activity and molecular docking studies of some new quinolines as potent anticancer agents

Authors: Tuğba Kul Köprülü, Salih Ökten, Vildan Enisoğlu Atalay, Şaban Tekin, Osman Çakmak

Published in: Medical Oncology | Issue 7/2021

Abstract

The objective of this study is to investigate the antiproliferative and cytotoxic properties and the action mechanism of substituted quinoline and tetrahydroquinolines 3, 4, 5, 7, and 8 against rat glioblastoma (C6), human cervical cancer (HeLa), human adenocarcinoma (HT29) cancer cell lines by BrdU Cell Proliferation ELISA, Lactate Dehydrogenase, DNA laddering and Topoisomerase I assays. The results of the study showed that 6,8-dibromotetrahydroquinoline 3 possess in vitro antiproliferative activity against C6, HeLa, and HT29 cell lines while morpholine/piperazine substituted quinoline 7 and 8 showed selective antiproliferative activity on C6 cell line with IC₅₀ values 47.5 and 46.3 µg/mL, respectively. Moreover, 6,8-dibromoTHQ 3 caused DNA fragmentation while it did not inhibit the Topoisomerase I (Topo I) enzyme. On the other hand, compound 8 did not cause DNA laddering while 8 inhibited the Topo I enzyme. According to these results, 6,8-dibromoTHQ 3 stimulates apoptosis on the C6 cell line while 6,8-dibromo-3-morhonilylquinoline (8) inhibits the Topo I enzyme to cause antiproliferative activity.

Graphic abstract

Ökten S, Çakmak O, Tekin Ş. The SAR study of 6,8-disubstituted quinoline derivatives as anti cancer agents. Turk Clin Lab. 2017;8:152–9. https://doi.org/10.18663/tjcl.292058.CrossRef

Köprülü TK, Ökten S, Tekin Ş, Çakmak O. Biological evaluation of some quinoline derivatives with different functional groups as anticancer agents. J Biochem Mol Toxicol. 2019;33: e22260. https://doi.org/10.1002/jbt.22260.CrossRefPubMed

Solomon VR, Lee H. Quinoline as a privileged scaffold in cancer drug discovery. Curr Med Chem. 2011;18:1488–508. https://doi.org/10.2174/092986711795328382.CrossRefPubMed

Ökten S. Synthesis of aryl substituted quinolines and tetrahydroquinolines through Suzuki-Miyaura coupling reactions. J Chem Res. 2019;43:274–80. https://doi.org/10.1177/1747519819861389.CrossRef

Ökten S, Aydın A, Koçyiğit ÜM, Çakmak O, Erkan S, Andac CA, Taslimi P, Gülçin İ. Quinoline-based promising anticancer and antibacterial agents, and some metabolic enzymes inhibitors. Arch Pharm. 2020;353: e2000086. https://doi.org/10.1002/ardp.202000086.CrossRef

Modapa S, Tusi Z, Sridhar D, Kumar A, Siddiqi MI, Srivastava K, Rizvi A, Tripathi R, Puri SK, Keshava GS, Shukla PK, Batra S. Search for new pharmacophores for antimalarial activity. Part I: synthesis and antimalarial activity of new 2-methyl-6-ureido-4-quinolinamides. Bioorg Med Chem. 2009;17:203–21. https://doi.org/10.1016/j.bmc.2008.11.021.CrossRef

Jin G, Li Z, Xiao F, Qi X, Sun X. Optimization of activity localization of quinoline derivatives: Design, synthesis, and dual evaluation of biological activity for potential antitumor and antibacterial agents. Bioorg Chem. 2020;99: 103837. https://doi.org/10.1016/j.bioorg.2020.103837.CrossRefPubMed

Kumar S, Bawa S, Drabu S, Panda BP. Design and synthesis of 2-chloroquinoline derivatives as non-azoles antimycotic agents. Med Chem Res. 2011;20:1340–8. https://doi.org/10.1007/s00044-010-9463-6.CrossRef

Guo LJ, Wei CX, Jia JH, Zhao LM, Quan ZS. Design and synthesis of 5-alkoxy-[1,2,4]triazolo[4,3-a]quinoline derivatives with anticonvulsant activity. Eur J Med Chem. 2009;44:954–8. https://doi.org/10.1016/j.ejmech.2008.07.010.CrossRefPubMed

10.

Mukherjee S, Pal M. Medicinal chemistry of quinolines as emerging anti-inflammatory agents: an overview. Curr Med Chem. 2013;20:4386–410. https://doi.org/10.2174/09298673113209990170.CrossRefPubMed

11.

Hochegger P, Faist J, Seebacher W, Saf R, Maser P, Kaiser M, Weis R. Antiprotozoal activities of tetrazole-quinolines with aminopiperidine linker. Med Chem. 2019;15:409–16. https://doi.org/10.2174/1573406414666181015115101.CrossRefPubMed

12.

Çakmak O, Ökten S, Alımlı D, Ersanlı CC, Koçyiğit ÜM, Taslimi P. Novel piperazine and morpholine substituted quinolines: selective synthesis through activation of 3,6,8-tribromoquinoline, characterization and their some metabolic enzymes inhibition potentials. J Mol Struct. 2020;1220:1286662. https://doi.org/10.1016/j.molstruc.2020.128666.CrossRef

13.

Guardia C, Stephens D, Dang H, Quijada M, Larionov O, Lleonart R. Antiviral activity of novel quinoline derivatives against dengue virus serotype 2. Molecules. 2018;23:672–83. https://doi.org/10.3390/molecules23030672.CrossRefPubMedCentral

14.

Ökten S, Çakmak O, Erenler R, Tekin Ş, Yüce Ö. Simple and convenient preparation of novel 6,8-disubstituted quinoline derivatives and their promising anticancer activities. Turk J Chem. 2013;37:896–908. https://doi.org/10.3906/kim-1301-30.CrossRef

15.

Jain S, Chandra V, Jain PK, Pathak K, Pathak D, Vaidya A. Comprehensive review on current developments of quinoline-based anticancer agents. Arab J Chem. 2019;12:4920–46. https://doi.org/10.1016/j.arabjc.2016.10.009.CrossRef

16.

Afzal O, Kumar S, Haider MR, Ali MR, Kumar R, Jaggi M, Bawa S. A review on anticancer potential of bioactive heterocycle quinoline. Eur J Med Chem. 2015;97:871–910. https://doi.org/10.1016/j.ejmech.2014.07.044.CrossRefPubMed

17.

Köprülü TK, Tekin, Ökten S, Çınar M, Duman S, Çakmak O. Detection of mechanism and anticancer activity of the new quinoline compounds MC20 and MC21. J Biotechnol. 2014;185:93. https://doi.org/10.1016/j.jbiotec.2014.07.318.CrossRef

18.

Ökten S, Şahin ÖY, Tekin Ş, Çakmak O. In vitro antiproliferative/cytotoxic activity of novel quinoline compound SO-18 against various cancer cell lines. J Biotechnol. 2014;185:106. https://doi.org/10.1016/j.jbiotec.2014.07.359.CrossRef

19.

Aydın A, Ökten S, Erkan S, Bulut M, Özcan E, Tutar A, Eren T. In vitro anticancer and antibacterial activities of brominated indenoquinoline amines supported with molecular docking and MCDM. ChemistrySelect. 2021;6:3286–95. https://doi.org/10.1002/slct.202004753.CrossRef

20.

Arafa RK, Hegazy GH, Piazza GA, Abadi AH. Synthesis and in vitro antiproliferative effect of novel quinoline-based potential anticancer agents. Eur J Med Chem. 2013;63:826–32. https://doi.org/10.1016/j.ejmech.2013.03.008.CrossRefPubMed

21.

Alqasoumi SI, Al-Taweel AM, Alafeefy AM, Hamed MM, Noaman E, Ghorab MM. Synthesis and biological evaluation of 2-amino-7,7-dimethyl 4-substituted-5-oxo-1-(3,4,5-trimethoxy)-1,4,5,6,7,8-hexahydro-quinoline-3-carbonitrile derivatives as potential cytotoxic agents. Bioorg Med Chem Lett. 2009;19:6939–42. https://doi.org/10.1016/j.bmcl.2009.10.065.CrossRefPubMed

22.

Ghorab MM, Ragab FA, Heiba HI, Arafa RK, El-Hossary EM. In vitro anticancer screening and radiosensitizing evaluation of some new quinolines and pyrimido[4,5-b]quinolines bearing a sulfonamide moiety. Eur J Med Chem. 2010;45:3677–84. https://doi.org/10.1016/j.ejmech.2010.05.014.CrossRefPubMed

23.

Wang Y, Ai J, Wang Y, Chen Y, Wang L, Liu G, Geng M, Zhang A. Synthesis and c-Met kinase inhibition of 3,5-disubstituted and 3,5,7-trisubstituted quinolines: Identification of 3-(4-acetylpiperazin-1-yl)-5-(3-nitrobenzylamino)-7- (trifluoromethyl)quinoline as a novel anticancer agent. J Med Chem. 2011;54:2127–42. https://doi.org/10.1021/jm101340q.CrossRefPubMed

24.

Ghorab MM, Ragab FA, Heiba HI, Ghorab WM. Design and synthesis of some novel quinoline derivatives as anticancer and radiosensitizing agents targeting VEGFR tyrosine kinase. J Heterocycl Chem. 2011;48:1269–79. https://doi.org/10.1002/jhet.749.CrossRef

25.

Tseng C, Chen Y, Chung K, Wang C, Peng S, Cheng C, Tzeng C. Synthesis and antiproliferative evaluation of 2,3-diarylquinoline derivatives. Org Biomol Chem. 2011;9:3205–16. https://doi.org/10.1039/c0ob01225d.CrossRefPubMed

26.

Ökten S, Çakmak O, Tekin Ş, Köprülü TK. A SAR Study: Evaluation of bromo derivatives of 8-substituted quinolines as novel anticancer agents. Lett Drug Des Discov. 2017;14(12):1415–24. https://doi.org/10.2174/1570180814666170504150050.CrossRef

27.

Hyatt JL, Tsurkan L, Morton CL, Yoon KJ, Harel M, Brumshtein B, Silman I, Sussman JL, Wadkins RM, Potter PM. Inhibition of acetylcholinesterase by the anticancer prodrug CPT-11. Chem Biol Interact. 2005;157–158:247–52. https://doi.org/10.1016/j.cbi.2005.10.033.CrossRefPubMed

28.

Atsumi S, Nosaka C, Ochi Y, Iinuma H, Umezawa K. Inhibition of experimental metastasis by an alpha-glucosidase inhibitor, 1,6-epi-cyclophellitol. Cancer Res. 1993;53(20):4896–9.PubMed

29.

Bernacki RJ, Niedhala MJ, Korytnyk W. Glycosidases in cancer and invasion. Cancer Metastasis Rev. 1985;4(1):81–101. https://doi.org/10.1007/BF00047738.CrossRefPubMed

30.

Supuran CT, Scozzafava A. Carbonic anhydrase inhibitors and their therapeutic potential. Expert Opin Ther Pat. 2000;10(5):575–600. https://doi.org/10.1517/13543776.10.5.575.CrossRef

31.

Thiry A, Dogné JM, Masereel B, Supuran CT. Targeting tumor-associated carbonic anhydrase IX in cancer therapy. Trends Pharmacol Sci. 2006;27(11):566–73. https://doi.org/10.1016/j.tips.2006.09.002.CrossRefPubMed

32.

Singh S, Lomelino CL, Mboge MY, Frost SC, McKenna R. Cancer drug development of carbonic anhydrase ınhibitors beyond the active site. Molecules. 2018;23(5):1045. https://doi.org/10.3390/molecules23051045.CrossRefPubMedCentral

33.

Supuran CT. Therapeutic applications of the carbonic anhydrase inhibitors. Therapy. 2007;4(3):355–78. https://doi.org/10.2217/14750708.4.3.355.CrossRef

34.

Şahin A, Çakmak O, Demirtaş I, Ökten S, Tutar A. Efficent and selective synthesis of quinoline derivatives. Tetrahedron. 2008;64:10068–74. https://doi.org/10.1016/j.tet.2008.08.018.CrossRef

35.

Çakmak O, Ökten S, Alımlı D, Saddiqa A, Ersanlı CC. Activation of 6-bromoquinoline by nitration: synthesis of morpholinyl and piperazinyl quinolines. ARKIVOC. 2018;3:362–74.

36.

Gong J, Traganos F, Darzynkiewicz Z. A selective procedure for DNA extraction from apoptotic cells applicable for gel electrophoresis and flow cytometry. Anal Biochem. 1994;218:314–9. https://doi.org/10.1006/abio.1994.1184.CrossRefPubMed

37.

Ökten S, Erenler R, Köprülü TK, Tekin Ş. In vitro antiproliferative/cytotoxic activity of 2,3’-biindole against various cancer cell lines. Turk J Biol. 2015;39:15–22. https://doi.org/10.3906/biy-1402-60.CrossRef

38.

Stewart JJ. Application of the PM6 method to modeling the solid state. J Mol Model. 2008;14:499–535. https://doi.org/10.1007/s00894-008-0299-7.CrossRefPubMedPubMedCentral

39.

Kong J, White CA, Krylov AI, Sherrill CD, Adamson RD, Furlani TR, Lee MS, Lee AM, Gwaltney SR, Adams TR, Ochsenfeld C, Gilbert ATB, Kedziora GS, Rassolov VA, Maurice DR, Nair N, Shao Y, Besley NA, Maslen PE, Dombroski JP, Daschel H, Zhang W, Korambath PP, Baker J, Byrd EFC, Voorhis TV, Oumi M, Hirata S, Hsu CP, Ishikawa N, Florian J, Warshel A, Johnson BG, Gill PGM, Gordon, MH, Pople JA. Q-Chem 2.0: a high‐performance ab initio electronic structure program package. J Comput Chem. 2000;21:1532–48. https://doi.org/10.1002/1096-987X(200012)21:16<1532::AID-JCC10>3.0.CO;2-W.CrossRef

40.

Stewart JJP. Application of the PM6 method to modeling proteins. J Mol Model. 2009;15:765. https://doi.org/10.1007/s00894-008-0420-y.CrossRefPubMed

41.

Frisch MJ, Trucks GW, Schlegel HB, Suzerain GE, Robb MA, Cheeseman JR, Montgomery JA, Vreven T, Kudin KN, Burant JC, Millam JM, Iyengar SS, Tomasi J, Barone V, Mennucci B, Cossi M, Scalmani G, Rega N, Petersson GA, Nakatsuji H, Hada M, Ehara M, Toyota K, Fukuda R, Hasegawa J, Ishida M, Nakajima T, Honda Y, Kitao O, Nakai H, Klene M, Li X, Knox JE, Hratchian HP, Cross JB, Bakken V, Adamo C, Jaramillo J, Gomperts R, Stratmann RE, Yazyev O, Austin AJ, Cammi R, Pomelli C, Ochterski JW, Ayala PY, Morokuma K, Voth GA, Salvador P, Dannenberg JJ, Zakrzewski VG, Dapprich S, Daniels AD, Strain MC, Farkas O, Malick DK, Rabuck AD, Raghavachari K, Foresman JB, Ortiz JV, Cui Q, Baboul AG, Clifford S, Cioslowski J, Stefanov B, Liu G, Liashenko A, Piskorz P, Komaromi I, Martin RL, Fox DJ, Keith T, Al-Laham MA, Peng CY, Nanayakkara A, Challacombe M, Gill PMW, Johnson B, Chen W, Wong MW, Gonzalez C, Pople JA. Gaussian 09 (now Gaussian 16). Wallingford (CT): Gaussian Inc.; 2016.

42.

Cosconati S, Forli S, Perryman AL, Harris R, Goodsell DS, Olson AJ. Virtual screening with AutoDock: theory and practice. Expert Opin Drug Discov. 2010;5:597–607. https://doi.org/10.1517/17460441.2010.484460.CrossRefPubMedPubMedCentral

43.

Forli S, Olson AJ. A force field with discrete displaceable waters and desolvation entropy for hydrated ligand docking. J Med Chem. 2012;55:623–38. https://doi.org/10.1021/jm2005145.CrossRefPubMedPubMedCentral

44.

Lattanzio R, Iezzi M, Sala G, Tinari N, Falasca M, Alberti S, Buglioni S, Mottolese M, Perracchio L, Natali PG, Piantelli M. PLC-gamma-1 phosphorylation status is prognostic of metastatic risk in patients with early-stage Luminal-A and -B breast cancer subtypes. BMC Cancer. 2019;19:747. https://doi.org/10.1186/s12885-019-5949-x.CrossRefPubMedPubMedCentral

45.

Sala G, Dituri F, Raimondi C, Previdi S, Maffucci T, Mazzoletti M, Rossi C, Iezzi M, Lattanzio R, Piantelli M, Iacobelli S, Broggini M, Falasca M. Phospholipase Cγ1 Is Required for Metastasis Development and Progression. Cancer Res. 2008;68:10187. https://doi.org/10.1158/0008-5472.CAN-08-1181.CrossRefPubMed

46.

Bunney TD, Esposito D, Mas-Droux C, Lamber E, Baxendale RW, Martins M, Cole A, Svergun D, Driscoll PC, Katan M. Structural and functional integration of the PLCγ interaction domains critical for regulatory mechanisms and signaling deregulation. Structure. 2012;20:2062–75. https://doi.org/10.1016/j.str.2012.09.005.CrossRefPubMedPubMedCentral

Title: Biological activity and molecular docking studies of some new quinolines as potent anticancer agents
Authors: Tuğba Kul Köprülü
Salih Ökten
Vildan Enisoğlu Atalay
Şaban Tekin
Osman Çakmak
Publication date: 01-07-2021
Publisher: Springer US
Keyword: Piperazine
Published in: Medical Oncology / Issue 7/2021
Print ISSN: 1357-0560
Electronic ISSN: 1559-131X
DOI: https://doi.org/10.1007/s12032-021-01530-w

Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Reserve your place

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin

Prof. Florian Limbourg

Prof. Anoop Chauhan

Developed by: Springer Medicine

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discusses last year's major advances in heart failure and cardiomyopathies.

Watch now

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

Illustration of figure on mountain summit/© Orapun / Stock.adobe.com, STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Graphic abstract

Please log in to get access to this content

Other articles of this Issue 7/2021

Identification of key genes in the tumor microenvironment of lung adenocarcinoma

Upfront metastasis‑directed therapy in oligorecurrent prostate cancer does not decrease the time from initiation of androgen deprivation therapy to castration resistance: in regard to Triggiani et al.

How should we manage non-small-cell lung cancer “not-otherwise-specified”?

ceRNA network development and tumor-infiltrating immune cell analysis in hepatocellular carcinoma

Systematic identification of the cancer pathways and molecules related with breast cancer immunogenicity

Correction to: Diosmetin induces apoptosis in ovarian cancer cells by activating reactive oxygen species and inhibiting the Nrf2 pathway

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage