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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

Synthesis, Molecular Docking, and 2D-QSAR Modeling of Quinoxaline Derivatives as Potent Anticancer Agents against Triple-negative Breast Cancer

Author(s): Tanu Kaushal, Sana Khan, Kaneez Fatima, Suaib Luqman, Feroz Khan* and Arvind Singh Negi*

Volume 22, Issue 10, 2022

Published on: 26 May, 2022

Page: [855 - 867] Pages: 13

DOI: 10.2174/1568026622666220324151808

Price: $65

Abstract

Background: Breast carcinomas aka triple-negative breast cancers (TNBC) are one of the most complex and aggressive forms of cancers in females. Recently, studies have shown that these carcinomas are resistant to hormone-targeted therapies, which makes it a priority to search for effective and potential anticancer drugs. The present study aimed to synthesize and develop the 2Dquantitative structural activity relationship model (QSAR) of quinoxaline derivatives as a potential anticancer agent.

Methods: Quinoxaline derivatives were designed and synthesized (8a-8i and 9a-9d) and the 2DQSAR model against TNBC was developed using VLife MDS v4.4. The anticancer activity was investigated against the TNBC MDA-MB-231 cell line using an MTT cytotoxicity assay. Molecular docking studies along with the estimation of ADMET parameters were done using Discovery Studio. The most potent compound was docked against the β-tubulin protein target (PDB: 4O2B), using the Autodock Vina v0.8 program.

Results: Eleven derivatives of quinoxaline were designed and synthesized (8a-8i and 9a-9d) and a 2D-QSAR model was developed against the TNBC MDA-MB231 cell line. The regression coefficient values for the training set were (r2) 0.78 and (q2) 0.71. Further, external test set regression (pred_r2) was 0.68. Five molecular descriptors viz., energy dispersive (Epsilon3), protein-coding gene (T_T_C_6), molecular force field (MMFF_6), most hydrophobic hydrophilic distance (XA), and Zcomp Dipole were identified. After ADMET, the best analog 8a showed the best activity against the TNBC cell line. The best-predicted hit '8a' was found to bind within the active site of the β- tubulin protein target.

Conclusion: The newly synthesized quinoxaline compounds could serve as potent leads for the development of novel anti-cancer agents against TNBC.

Keywords: Breast cancer, Molecular Docking, QSAR, Multiple Linear Regression Modeling, Anti-cancer agents, Triplenegative breast cancer.

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[1]
WHO cancer factsheet 2018.
[2]
Wu, G.; Wilson, G.; George, J.; Liddle, C.; Hebbard, L.; Qiao, L. Overcoming treatment resistance in cancer: Current understanding and tactics. Cancer Lett., 2017, 387, 69-76.
[http://dx.doi.org/10.1016/j.canlet.2016.04.018] [PMID: 27089987]
[3]
El-Atawy, M.A.; Hamed, E.A.; Alhadi, M.; Omar, A.Z. Synthesis and antimicrobial activity of some new substituted quinoxalines. Molecules, 2019, 24(22), 4198.
[http://dx.doi.org/10.3390/molecules24224198] [PMID: 31752396]
[4]
Chandra Shekhar, A.; Shanthan Rao, P.; Narsaiah, B.; Allanki, A.D.; Sijwali, P.S. Emergence of pyrido quinoxalines as new family of antimalarial agents. Eur. J. Med. Chem., 2014, 77, 280-287.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.010] [PMID: 24650715]
[5]
Bonilla-Ramirez, L.; Rios, A.; Quiliano, M.; Ramirez-Calderon, G.; Beltrán-Hortelano, I.; Franetich, J.F.; Corcuera, L.; Bordessoulles, M.; Vettorazzi, A.; López de Cerain, A.; Aldana, I.; Mazier, D.; Pabón, A.; Galiano, S. Novel antimalarial chloroquine- and primaquine-quinoxaline 1,4-di-N-oxide hybrids: Design, synthesis, Plasmodium life cycle stage profile, and preliminary toxicity studies. Eur. J. Med. Chem., 2018, 158, 68-81.
[http://dx.doi.org/10.1016/j.ejmech.2018.08.063] [PMID: 30199706]
[6]
Kaushal, T.; Srivastava, G.; Sharma, A.; Singh Negi, A. An insight into medicinal chemistry of anticancer quinoxalines. Bioorg. Med. Chem., 2019, 27(1), 16-35.
[http://dx.doi.org/10.1016/j.bmc.2018.11.021] [PMID: 30502116]
[7]
Parhi, A.K.; Zhang, Y.; Saionz, K.W.; Pradhan, P.; Kaul, M.; Trivedi, K.; Pilch, D.S.; LaVoie, E.J. Antibacterial activity of quinoxalines, quinazolines, and 1,5-naphthyridines. Bioorg. Med. Chem. Lett., 2013, 23(17), 4968-4974.
[http://dx.doi.org/10.1016/j.bmcl.2013.06.048] [PMID: 23891185]
[8]
Zhang, M.; Dai, Z.C.; Qian, S.S.; Liu, J.Y.; Xiao, Y. Design, synthesis, antifungal, and antioxidant activities of (E)-6((2-Phenylhydrazono) methyl) quinoxaline-Phenylhydrazono) methyl) quinoxaline derivatives. J. Agric. Food Chem., 2014, 62, 9637-9643.
[http://dx.doi.org/10.1021/jf504359p] [PMID: 25229541]
[9]
Ingle, R.; Marathe, R.; Magar, D.; Patel, H.M.; Surana, S.J. Sulphonamido-quinoxalines: Search for anticancer agent. Eur. J. Med. Chem., 2013, 65, 168-186.
[http://dx.doi.org/10.1016/j.ejmech.2013.04.028] [PMID: 23708011]
[10]
Abid, M.; Azam, A. Synthesis, characterization and antiamoebic activity of 1-(thiazolo[4,5-b]quinoxaline-2-yl)-3-phenyl-2-pyrazo- line derivatives. Bioorg. Med. Chem. Lett., 2006, 16(10), 2812-2816.
[http://dx.doi.org/10.1016/j.bmcl.2006.01.116] [PMID: 16495051]
[11]
Zarnowski, T.; Kleinrok, Z.; Turski, W.A.; Czuczwar, S.J. 2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)quinoxaline enhances the protective activity of common antiepileptic drugs against maximal electroshock-induced seizures in mice. Neuropharmacology, 1993, 32(9), 895-900.
[http://dx.doi.org/10.1016/0028-3908(93)90145-S] [PMID: 7694171]
[12]
Elhelby, A.A.; Ayyad, R.R.; Zayed, M.F. Synthesis and biological evaluation of some novel quinoxaline derivatives as anticonvulsant agents. Arzneimittelforschung, 2011, 61(7), 379-381.
[http://dx.doi.org/10.1055/s-0031-1296214] [PMID: 21899204]
[13]
Wang, T.; Tang, Y.; Yang, Y.; An, Q.; Sang, Z.; Yang, T.; Liu, P.; Zhang, T.; Deng, Y.; Luo, Y. Discovery of novel anti-tuberculosis agents with pyrrolo[1,2-a]quinoxaline-based scaffold. Bioorg. Med. Chem. Lett., 2018, 28(11), 2084-2090.
[http://dx.doi.org/10.1016/j.bmcl.2018.04.043] [PMID: 29748048]
[14]
Desplat, V.; Moreau, S.; Belisle-Fabre, S.; Thiolat, D.; Uranga, J.; Lucas, R.; de Moor, L.; Massip, S.; Jarry, C.; Mossalayi, D.M.; Sonnet, P.; Déléris, G.; Guillon, J. Synthesis and evaluation of the antiproliferative activity of novel isoindolo[2,1-a]quinoxaline and indolo[1,2-a]quinoxaline derivatives. J. Enzyme Inhib. Med. Chem., 2011, 26(5), 657-667.
[http://dx.doi.org/10.3109/14756366.2010.548326] [PMID: 21250818]
[15]
Yan, W.; Qing, J.; Mei, H.; Mao, F.; Huang, J.; Zhu, J.; Jiang, H.; Liu, L.; Zhang, L.; Li, J. Discovery of novel small molecule anti-HCV agents via the CypA inhibitory mechanism using O-acylation-directed lead optimization. Molecules, 2015, 20(6), 10342-10359.
[http://dx.doi.org/10.3390/molecules200610342] [PMID: 26053489]
[16]
Shen, Q.K.; Gong, G.H.; Li, G.; Jin, M.; Cao, L.H.; Quan, Z.S. Discovery and evaluation of novel synthetic 5-alkyl-4-oxo-4,5-dihydro-[1,2,4]triazolo[4,3-a]quinoxaline-1-carbox-amide derivatives as anti-inflammatory agents. J. Enzyme Inhib. Med. Chem., 2020, 35(1), 85-95.
[http://dx.doi.org/10.1080/14756366.2019.1680658] [PMID: 31707866]
[17]
Watanabe, K.; Oguri, H.; Oikawa, H. Diversification of echinomycin molecular structure by way of chemoenzymatic synthesis and heterologous expression of the engineered echinomycin biosynthetic pathway. Curr. Opin. Chem. Biol., 2009, 13(2), 189-196.
[http://dx.doi.org/10.1016/j.cbpa.2009.02.012] [PMID: 19278894]
[18]
Toris, C.B.; Camras, C.B.; Yablonski, M.E. Acute versus chronic effects of brimonidine on aqueous humor dynamics in ocular hypertensive patients. Am. J. Ophthalmol., 1999, 128(1), 8-14.
[http://dx.doi.org/10.1016/S0002-9394(99)00076-8] [PMID: 10482088]
[19]
Sena, D.F.; Lindsley, K. Neuroprotection for treatment of glaucoma in adults. Cochrane Database Syst. Rev., 2013, 2(2)CD006539
[PMID: 23450569]
[20]
Polyak, K. Heterogeneity in breast cancer. J. Clin. Invest., 2011, 121(10), 3786-3788.
[http://dx.doi.org/10.1172/JCI60534] [PMID: 21965334]
[21]
Ovcaricek, T.; Frkovic, S.G.; Matos, E.; Mozina, B.; Borstnar, S. Triple negative breast cancer - prognostic factors and survival. Radiol. Oncol., 2011, 45(1), 46-52.
[http://dx.doi.org/10.2478/v10019-010-0054-4] [PMID: 22933934]
[22]
Bianchini, G.; Balko, J.M.; Mayer, I.A.; Sanders, M.E.; Gianni, L. Triple-negative breast cancer: Challenges and opportunities of a heterogeneous disease. Nat. Rev. Clin. Oncol., 2016, 13(11), 674-690.
[http://dx.doi.org/10.1038/nrclinonc.2016.66] [PMID: 27184417]
[23]
Thike, A.A.; Iqbal, J.; Cheok, P.Y.; Chong, A.P.; Tse, G.M.; Tan, B.; Tan, P.; Wong, N.S.; Tan, P.H. Triple negative breast cancer: Outcome correlation with immunohistochemical detection of basal markers. Am. J. Surg. Pathol., 2010, 34(7), 956-964.
[http://dx.doi.org/10.1097/PAS.0b013e3181e02f45] [PMID: 20495445]
[24]
Canel, C.; Moraes, R.M.; Dayan, F.E.; Ferreira, D. Podophyllotoxin. Phytochemistry, 2000, 54(2), 115-120.
[http://dx.doi.org/10.1016/S0031-9422(00)00094-7] [PMID: 10872202]
[25]
Jaroch, K.; Karolak, M.; Górski, P.; Jaroch, A.; Krajewski, A.; Ilnicka, A.; Sloderbach, A. Stefański, T.; Sobiak, S. Combretastatins: In vitro structure-activity relationship, mode of action and current clinical status. Pharmacol. Rep., 2016, 68(6), 1266-1275.
[http://dx.doi.org/10.1016/j.pharep.2016.08.007] [PMID: 27686966]
[26]
Lu, Y.; Chen, J.; Xiao, M.; Li, W.; Miller, D.D. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res., 2012, 29(11), 2943-2971.
[http://dx.doi.org/10.1007/s11095-012-0828-z] [PMID: 22814904]
[27]
McNulty, J.; van den Berg, S.; Ma, D.; Tarade, D.; Joshi, S.; Church, J.; Pandey, S. Antimitotic activity of structurally simplified biaryl analogs of the anticancer agents colchicine and combretastatin A4. Bioorg. Med. Chem. Lett., 2015, 25(1), 117-121.
[http://dx.doi.org/10.1016/j.bmcl.2014.10.090] [PMID: 25466200]
[28]
Srivastava, V.; Negi, A.S.; Kumar, J.K.; Gupta, M.M.; Khanuja, S.P. Plant-based anticancer molecules: A chemical and biological profile of some important leads. Bioorg. Med. Chem., 2005, 13(21), 5892-5908.
[http://dx.doi.org/10.1016/j.bmc.2005.05.066] [PMID: 16129603]
[29]
Desbène, S.; Giorgi-Renault, S. Drugs that inhibit tubulin polymerization: The particular case of podophyllotoxin and analogues. Curr. Med. Chem. Anticancer Agents, 2002, 2(1), 71-90.
[http://dx.doi.org/10.2174/1568011023354353] [PMID: 12678752]
[30]
Negi, A.S.; Gautam, Y.; Alam, S.; Chanda, D.; Luqman, S.; Sarkar, J.; Khan, F.; Konwar, R. Natural antitubulin agents: Importance of 3,4,5-trimethoxyphenyl fragment. Bioorg. Med. Chem., 2015, 23(3), 373-389.
[http://dx.doi.org/10.1016/j.bmc.2014.12.027] [PMID: 25564377]
[31]
Eldehna, W.M.; Almahli, H.; Al-Ansary, G.H.; Ghabbour, H.A.; Aly, M.H.; Ismael, O.E.; Al-Dhfyan, A.; Abdel-Aziz, H.A. Synthesis and in vitro anti-proliferative activity of some novel isatins conjugated with quinazoline/phthalazine hydrazines against triple-negative breast cancer MDA-MB-231 cells as apoptosis-inducing agents. J. Enzyme Inhib. Med. Chem., 2017, 32(1), 600-613.
[http://dx.doi.org/10.1080/14756366.2017.1279155] [PMID: 28173708]
[32]
Rhee, H.K.; Yoo, J.H.; Lee, E.; Kwon, Y.J.; Seo, H.R.; Lee, Y.S.; Choo, H.Y. Synthesis and cytotoxicity of 2-phenylquinazolin-4(3H)-one derivatives. Eur. J. Med. Chem., 2011, 46(9), 3900-3908.
[http://dx.doi.org/10.1016/j.ejmech.2011.05.061] [PMID: 21704436]
[33]
Mahdavi, M.; Pedrood, K.; Safavi, M.; Saeedi, M.; Pordeli, M.; Ardestani, S.K.; Emami, S.; Adib, M.; Foroumadi, A.; Shafiee, A. Synthesis and anticancer activity of N-substituted 2-arylquinazolinones bearing trans-stilbene scaffold. Eur. J. Med. Chem., 2015, 95(5), 492-499.
[http://dx.doi.org/10.1016/j.ejmech.2015.03.057] [PMID: 25847767]
[34]
Cramer, R.D., III; Bunce, J.D.; Patterson, D.E.; Frank, I.E. Crossvalidation, bootstrapping, and partial least squares compared with multiple regression in conventional QSAR studies. Quant. Stru. Act. Rel., 1988, 7(1), 18-25.
[http://dx.doi.org/10.1002/qsar.19880070105]
[35]
Golbraikh, A.; Tropsha, A. Beware of q2! J. Mol. Graph. Model., 2002, 20(4), 269-276.
[http://dx.doi.org/10.1016/S1093-3263(01)00123-1] [PMID: 11858635]
[36]
Ojha, P.K.; Mitra, I.; Das, R.N.; Roy, K. Further exploring rm2 metrics for validation of QSPR models. Chemom. Intell. Lab. Syst., 2011, 107(1), 194-205.
[http://dx.doi.org/10.1016/j.chemolab.2011.03.011]
[37]
Shen, M.; LeTiran, A.; Xiao, Y.; Golbraikh, A.; Kohn, H.; Tropsha, A. Quantitative structure-activity relationship analysis of functionalized amino acid anticonvulsant agents using k nearest neighbor and simulated annealing PLS methods. J. Med. Chem., 2002, 45(13), 2811-2823.
[http://dx.doi.org/10.1021/jm010488u] [PMID: 12061883]
[38]
Kier, L.B.; Hall, L.H. Nature of structure-activity-relationships and their relation to molecular connectivity. Eur. J. Med. Chem., 1977, 12, 307-312.
[39]
Parihar, S.; Gupta, A.; Chaturvedi, A.K.; Agarwal, J.; Luqman, S.; Changkija, B.; Manohar, M.; Chanda, D.; Chanotiya, C.S.; Shanker, K.; Dwivedi, A.; Konwar, R.; Negi, A.S. Gallic acid based steroidal phenstatin analogues for selective targeting of breast cancer cells through inhibiting tubulin polymerization. Steroids, 2012, 77(8-9), 878-886.
[http://dx.doi.org/10.1016/j.steroids.2012.03.012] [PMID: 22503714]
[40]
Lipinski, C.A.; Lombardo, F.; Dominy, B.W.; Feeney, P.J. Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv. Drug Deliv. Rev., 2001, 46(1-3), 3-26.
[http://dx.doi.org/10.1016/S0169-409X(00)00129-0] [PMID: 11259830]
[41]
Meena, A.; Yadav, D.K.; Srivastava, A.; Khan, F.; Chanda, D.; Chattopadhyay, S.K. In silico exploration of anti-inflammatory activity of natural coumarinolignoids. Chem. Biol. Drug Des., 2011, 78(4), 567-579.
[http://dx.doi.org/10.1111/j.1747-0285.2011.01173.x] [PMID: 21736704]
[42]
Shukla, A.; Tyagi, R.; Meena, S.; Datta, D.; Srivastava, S.K.; Khan, F. 2D- and 3D-QSAR modelling, molecular docking and in vitro evaluation studies on 18β-glycyrrhetinic acid derivatives against triple-negative breast cancer cell line. J. Biomol. Struct. Dyn., 2020, 38(1), 168-185.
[http://dx.doi.org/10.1080/07391102.2019.1570868] [PMID: 30686140]
[43]
Burns, R.G. Analysis of the colchicine-binding site of beta-tubulin. FEBS Lett., 1992, 297(3), 205-208.
[http://dx.doi.org/10.1016/0014-5793(92)80538-R] [PMID: 1544399]
[44]
Cheng, J.F.; Chen, M.; Wallace, D.; Tith, S.; Arrhenius, T.; Kashiwagi, H.; Ono, Y.; Ishikawa, A.; Sato, H.; Kozono, T.; Sato, H.; Nadzan, A.M. Discovery and structure-activity relationship of coumarin derivatives as TNF-alpha inhibitors. Bioorg. Med. Chem. Lett., 2004, 14(10), 2411-2415.
[http://dx.doi.org/10.1016/S0960-894X(04)00355-5] [PMID: 15109623]
[45]
Brown, E.; Yedjou, C.G.; Tchounwou, P.B. Cytotoxicity and oxidative stress in human liver carcinoma cells exposed to arsenic trioxide (HepG(2)). Met. Ions Biol. Med., 2008, 10, 583-587.
[PMID: 20657712]

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