Login Register Cart 0
Generic placeholder image

Current Computer-Aided Drug Design

Editor-in-Chief

ISSN (Print): 1573-4099
ISSN (Online): 1875-6697

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Synthesis, In vitro, and Docking Analysis of C-3 Substituted Coumarin Analogues as Anticancer Agents

Author(s): Anuradha Thakur, Kamalpreet Kaur, Praveen Sharma, Ramit Singla, Sandeep Singh and Vikas Jaitak*

Volume 17, Issue 2, 2021

Published on: 20 January, 2020

Page: [161 - 172] Pages: 12

DOI: 10.2174/1573409916666200120114641

Price: $65

Abstract

Background: Breast cancer (BC) is a leading cause of cancer-related deaths in women next to skin cancer. Estrogen receptors (ERs) play an important role in the progression of BC. Current anticancer agents have several drawbacks such as serious side effects and the emergence of resistance to chemotherapeutic drugs. As coumarins possess minimum side effects along with multidrug reversal activity, it has a tremendous ability to regulate a diverse range of cellular pathways that can be explored for selective anticancer activity.

Objectives: Synthesis and evaluation of new coumarin analogues for anti-proliferative activity on human breast cancer cell line MCF-7 along with exploration of binding interaction of the compounds for ER-α target protein by molecular docking.

Methods: In this study, the anti-proliferative activity of C-3 substituted coumarins analogues (1-17) has been evaluated against estrogen receptor-positive MCF-7 breast cancer cell lines. Molecular interactions and ADME study of the compounds were analyzed by using Schrodinger software.

Results: Among the synthesized analogues, 12 and 13 show good antiproliferative activity with IC50 values 1 and 1.3 μM, respectively. Molecular docking suggests a remarkable binding pose of all the seventeen compounds. Compounds 12 and 13 were found to exhibit a docking score of -4.10 kcal/mol and -4.38 kcal/mol, respectively.

Conclusion: Compounds 12 and 13 showed the highest activity followed by 1 and 5. ADME properties of all compounds were in the acceptable range. The active compounds can be taken for lead optimization and mechanistic interventions for their in vivo study in the future.

Keywords: Coumarin, anticancer, breast cancer, estrogen receptor, molecular docking, ADME.

Next »
Graphical Abstract

[1]
Dadashpour, S.; Emami, S. Indole in the target-based design of anticancer agents: A versatile scaffold with diverse mechanisms. Eur. J. Med. Chem., 2018, 150, 9-29.
[http://dx.doi.org/10.1016/j.ejmech.2018.02.065] [PMID: 29505935]
[2]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2019. CA Cancer J. Clin., 2019, 69(1), 7-34.
[http://dx.doi.org/10.3322/caac.21551] [PMID: 30620402]
[3]
Spiegel, D.; Bloom, J.R.; Kraemer, H.C.; Gottheil, E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet, 1989, 2(8668), 888-891.
[http://dx.doi.org/10.1016/S0140-6736(89)91551-1] [PMID: 2571815]
[4]
Gelsomino, L.; Panza, S.; Giordano, C.; Barone, I.; Gu, G.; Spina, E.; Catalano, S.; Fuqua, S.; Andò, S. Mutations in the estrogen receptor alpha hormone binding domain promote stem cell phenotype through notch activation in breast cancer cell lines. Cancer Lett., 2018, 428, 12-20.
[http://dx.doi.org/10.1016/j.canlet.2018.04.023] [PMID: 29702197]
[5]
John, E.M.; Hines, L.M.; Phipps, A.I.; Koo, J.; Longacre, T.A.; Ingles, S.A.; Baumgartner, K.B.; Slattery, M.L.; Wu, A.H. Reproductive history, breast-feeding and risk of triple negative breast cancer: The Breast Cancer Etiology in Minorities (BEM) study. Int. J. Cancer, 2018, 142(11), 2273-2285.
[http://dx.doi.org/10.1002/ijc.31258] [PMID: 29330856]
[6]
Dunlap, T.L.; Howell, C.E.; Mukand, N.; Chen, S-N.; Pauli, G.F.; Dietz, B.M.; Bolton, J.L. Red clover aryl hydrocarbon receptor (AhR) and estrogen receptor (ER) agonists enhance genotoxic estrogen metabolism. Chem. Res. Toxicol., 2017, 30(11), 2084-2092.
[http://dx.doi.org/10.1021/acs.chemrestox.7b00237] [PMID: 28985473]
[7]
Tzagarakis-Foster, C.; Dishington, E. SUN-005 DAX-1 Inhibition of Estrogen Receptor and Metastasis Target Genes in Estrogen Receptor Positive Breast Cancer Cells. J. Endocr. Soc., 2019, 3(Supplement_1) SUN-005
[8]
Mills, J.N.; Rutkovsky, A.C.; Giordano, A. Mechanisms of resistance in estrogen receptor positive breast cancer: overcoming resistance to tamoxifen/aromatase inhibitors. Curr. Opin. Pharmacol., 2018, 41, 59-65.
[http://dx.doi.org/10.1016/j.coph.2018.04.009] [PMID: 29719270]
[9]
Srivastav, V.; Tiwari, M.; Zhang, X.; Yao, X. Synthesis and Antiretroviral Activity of 6-Acetyl-coumarin Derivatives against HIV-1 Infection. Indian J. Pharm. Sci., 2018, 80(1), 108-117.
[http://dx.doi.org/10.4172/pharmaceutical-sciences.1000335]
[10]
Kumar, M.; Singla, R.; Dandriyal, J.; Jaitak, V. Coumarin derivatives as anticancer agents for lung cancer therapy: a review. Anticancer. Agents Med. Chem., 2018, 18(7), 964-984.
[http://dx.doi.org/10.2174/1871520618666171229185926] [PMID: 29298657]
[11]
Thakur, A.; Singla, R.; Jaitak, V. Coumarins as anticancer agents: a review on synthetic strategies, mechanism of action and SAR studies. Eur. J. Med. Chem., 2015, 101, 476-495.
[http://dx.doi.org/10.1016/j.ejmech.2015.07.010] [PMID: 26188907]
[12]
Dandriyal, J.; Singla, R.; Kumar, M.; Jaitak, V. Recent developments of C-4 substituted coumarin derivatives as anticancer agents. Eur. J. Med. Chem., 2016, 119, 141-168.
[http://dx.doi.org/10.1016/j.ejmech.2016.03.087] [PMID: 27155469]
[13]
Bogdał, D. Coumarins: Fast synthesis by Knoevenagel condensation under microwave irradiation. J. Chem. Res. Synop., 1998, (8), 468-469.
[http://dx.doi.org/10.1039/a801724g]
[14]
Rong, L.; Li, X.; Wang, H.; Shi, D.; Tu, S.; Zhuang, Q. Efficient green procedure for the knoevenagel condensation under solvent‐free conditions. Synth. Commun., 2006, 36(16), 2407-2412.
[http://dx.doi.org/10.1080/00397910600640289]
[15]
van de Loosdrecht, A.A.; Beelen, R.H.; Ossenkoppele, G.J.; Broekhoven, M.G.; Langenhuijsen, M.M. A tetrazolium-based colorimetric MTT assay to quantitate human monocyte mediated cytotoxicity against leukemic cells from cell lines and patients with acute myeloid leukemia. J. Immunol. Methods, 1994, 174(1-2), 311-320.
[http://dx.doi.org/10.1016/0022-1759(94)90034-5] [PMID: 8083535]
[16]
Mirzayans, R.; Andrais, B.; Scott, A.; Tessier, A.; Murray, D. A sensitive assay for the evaluation of cytotoxicity and its pharmacologic modulation in human solid tumor-derived cell lines exposed to cancer-therapeutic agents. J. Pharm. Pharm. Sci., 2007, 10(2), 298s-311s.
[PMID: 17718933]
[17]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[18]
Twentyman, P.R.; Luscombe, M. A study of some variables in a tetrazolium dye (MTT) based assay for cell growth and chemosensitivity. Br. J. Cancer, 1987, 56(3), 279-285.
[http://dx.doi.org/10.1038/bjc.1987.190] [PMID: 3663476]
[19]
Vickers, P.J.; Dickson, R.B.; Shoemaker, R.; Cowan, K.H. A multidrug-resistant MCF-7 human breast cancer cell line which exhibits cross-resistance to antiestrogens and hormone-independent tumor growth in vivo. Mol. Endocrinol., 1988, 2(10), 886-892.
[http://dx.doi.org/10.1210/mend-2-10-886] [PMID: 3185565]
[20]
Sharma, K.; Srikant, C.B. Induction of wild-type p53, Bax, and acidic endonuclease during somatostatin-signaled apoptosis in MCF-7 human breast cancer cells. Int. J. Cancer, 1998, 76(2), 259-266.
[http://dx.doi.org/10.1002/(SICI)1097-0215(19980413)76:2<259::AID-IJC14>3.0.CO;2-7] [PMID: 9537589]
[21]
Halgren, T.A.; Murphy, R.B.; Friesner, R.A.; Beard, H.S.; Frye, L.L.; Pollard, W.T.; Banks, J.L. Glide: a new approach for rapid, accurate docking and scoring. 2. Enrichment factors in database screening. J. Med. Chem., 2004, 47(7), 1750-1759.
[http://dx.doi.org/10.1021/jm030644s] [PMID: 15027866]
[22]
Kawatkar, S.; Wang, H.; Czerminski, R.; Joseph-McCarthy, D. Virtual fragment screening: an exploration of various docking and scoring protocols for fragments using Glide. J. Comput. Aided Mol. Des., 2009, 23(8), 527-539.
[http://dx.doi.org/10.1007/s10822-009-9281-4] [PMID: 19495993]
[23]
Kellenberger, E.; Rodrigo, J.; Muller, P.; Rognan, D. Comparative evaluation of eight docking tools for docking and virtual screening accuracy. Proteins, 2004, 57(2), 225-242.
[http://dx.doi.org/10.1002/prot.20149] [PMID: 15340911]
[24]
Sastry, G.M.; Adzhigirey, M.; Day, T.; Annabhimoju, R.; Sherman, W. Protein and ligand preparation: parameters, protocols, and influence on virtual screening enrichments. J. Comput. Aided Mol. Des., 2013, 27(3), 221-234.
[http://dx.doi.org/10.1007/s10822-013-9644-8] [PMID: 23579614]
[25]
van de Waterbeemd, H.; Gifford, E. ADMET in silico modelling: towards prediction paradise? Nat. Rev. Drug Discov., 2003, 2(3), 192-204.
[http://dx.doi.org/10.1038/nrd1032] [PMID: 12612645]
[26]
Mousavi, S.H.; Davari, A-S.; Iranshahi, M.; Sabouri-Rad, S.; Tayarani Najaran, Z. Comparative analysis of the cytotoxic effect of 7-prenyloxycoumarin compounds and herniarin on MCF-7 cell line. Avicenna J. Phytomed., 2015, 5(6), 520-530.
[PMID: 26693409]
[27]
Zhang, T.; Yan, Z.; Li, Y-F.; Wang, N. Simplified aminocoumarin analogues as anticancer agents: Amino isosteric replacement in the noviose moiety resulted in substantial enhancement of antiproliferative activity. Chin. Chem. Lett., 2013, 24(8), 719-722.
[http://dx.doi.org/10.1016/j.cclet.2013.04.046]
[28]
Zhang, W.; Li, Z.; Zhou, M.; Wu, F.; Hou, X.; Luo, H.; Liu, H.; Han, X.; Yan, G.; Ding, Z.; Li, R. Synthesis and biological evaluation of 4-(1,2,3-triazol-1-yl)coumarin derivatives as potential antitumor agents. Bioorg. Med. Chem. Lett., 2014, 24(3), 799-807.
[http://dx.doi.org/10.1016/j.bmcl.2013.12.095] [PMID: 24418772]

Rights & Permissions Print Cite
Article Metrics
41
2
© 2024 Bentham Science Publishers | Privacy Policy