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Letters in Drug Design & Discovery


ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

Research Article

Synthesis, Molecular Docking, and Anticancer Activity of N-Heteroaryl Substituted Flavon Derivatives

Author(s): Bharti Sachin Fegade* and Shailaja Jadhav

Volume 20, Issue 12, 2023

Published on: 31 January, 2023

Page: [2055 - 2069] Pages: 15

DOI: 10.2174/1570180820666230111155456

Price: $65


Background: Flavones are potential anticancer agents that act by different mechanisms and have multiple targets to exert anticancer effects. Nitrogen-containing heterocyclic rings have remarkable chemical characteristics as well as a wide range of biological activities. Substitution of the N-heterocyclic ring on the flavon structure may potentiate its anticancer effect.

Objective: A series of flavon derivatives with an N-heteroaryl ring at the 4' position of the B ring of flavon were designed, prepared, and evaluated for anticancer activity.

Methods: Different flavon derivatives were created by cyclizing chalcones, and chalcones were synthesized by Claisen-Schmidt condensation of substituted aldehydes and 2-hydroxyacetophenone. Structures of all compounds were confirmed by 1HNMR, 13CNMR, FTIR, and MS spectra. Molecular docking was used to study the binding interactions of the synthesized compounds with the multiple targets ER-α, EGFR, and VEGFR-2. Anticancer activity was evaluated by Brine shrimp assay, MTT assay, and SRB assay on breast cancer (MCF-7, MDA-MB-231, and MDA-MB-468) and cervical cancer (HeLa). An apoptosis study was carried out on MCF-7 cell lines for the active compounds.

Results: Among all compounds, 6c and 5f showed potent growth inhibition of ER-positive breast cancer cell lines. Compounds 5b, 5c, 5g, and 6f displayed good anticancer activity against cervical cancer. In triple-negative breast cancer cell lines, compounds 5c, 6b, and 6c showed remarkable anticancer activity. The potent flavones identified against breast cancer cell lines were 5f and 6c. Anticancer study results were analogous to the results obtained by the molecular docking study.

Conclusion: This study offers a viable reference point for improving the design of flavon-incorporated Nheterocyclic ring derivatives as anticancer compounds.

Keywords: Claisen-Schmidt condensation, SRB assay, MTT assay, ER-α, EGFR, VEGFR-2.

Graphical Abstract
Tsao, A.S.; Kim, E.S.; Hong, W.K. Chemoprevention of cancer. CA Cancer J. Clin., 2004, 54(3), 150-180.
[] [PMID: 15195789]
Harborne, J.B.; Williams, C.A. Advances in flavonoid research since 1992. Phytochemistry, 2000, 55(6), 481-504.
[] [PMID: 11130659]
Le Marchand, L. Cancer preventive effects of flavonoids—A review. Biomed. Pharmacother., 2002, 56(6), 296-301.
[] [PMID: 12224601]
Kumar, S.; Pandey, A.K. Chemistry and biological activities of flavonoids: An overview. Scientific World Journal, 2013, 2013, 1-16.
[] [PMID: 24470791]
Jayashree, B.S.; Noor, F.A.; Yogendra, N.; Kumar, D.V. Synthesis of substituted 3-hydroxy flavones for antioxidant and antimicrobial activity. Pharmacology, 2008, 3, 586-595.
Gobbi, S.; Cavalli, A.; Rampa, A.; Belluti, F.; Piazzi, L.; Paluszcak, A.; Hartmann, R.W.; Recanatini, M.; Bisi, A. Lead optimization providing a series of flavone derivatives as potent nonsteroidal inhibitors of the cytochrome P450 aromatase enzyme. J. Med. Chem., 2006, 49(15), 4777-4780.
[] [PMID: 16854084]
Conti, C.; Mastromarino, P.; Sgro, R.; Desideri, N. Anti-picornavirus activity of synthetic flavon-3-yl esters. Antivir. Chem. Chemother., 1998, 9(6), 511-515.
[] [PMID: 9865389]
Swaminathan, M.; Chee, C.; Chin, S.; Buckle, M.; Rahman, N.; Doughty, S.; Chung, L. Flavonoids with M1 muscarinic acetylcholine receptor binding activity. Molecules, 2014, 19(7), 8933-8948.
[] [PMID: 24979399]
Danihelová, M.; Veverka, M.; Šturdík, E.; Jantová, S. Antioxidant action and cytotoxicity on HeLa and NIH-3T3 cells of new quercetin derivatives. Interdiscip. Toxicol., 2013, 6(4), 209-216.
[] [PMID: 24678260]
Aquila, S.; Giner, R.M.; Recio, M.C.; Spegazzini, E.D.; Ríos, J.L. Anti-inflammatory activity of flavonoids from Cayaponia tayuya roots. J. Ethnopharmacol., 2009, 121(2), 333-337.
[] [PMID: 19041703]
Mutoh, M.; Takahashi, M.; Fukuda, K.; Komatsu, H.; Enya, T.; Matsushima-Hibiya, Y.; Mutoh, H.; Sugimura, T.; Wakabayashi, K. Suppression by flavonoids of cyclooxygenase-2 promoter-dependent transcriptional activity in colon cancer cells: Structure-activity relationship. Jpn. J. Cancer Res., 2000, 91(7), 686-691.
[] [PMID: 10920275]
Doostdar, H.; Burke, M.D.; Mayer, R.T. Bioflavonoids: selective substrates and inhibitors for cytochrome P450 CYP1A and CYP1B1. Toxicology, 2000, 144(1-3), 31-38.
[] [PMID: 10781868]
Senderowicz, A.M. Flavopiridol: The first cyclin-dependent kinase inhibitor in human clinical trials. Invest. New Drugs, 1999, 17(3), 313-320.
[] [PMID: 10665481]
Senderowicz, A.M. Development of cyclin-dependent kinase modulators as novel therapeutic approaches for hematological malignancies. Leukemia, 2001, 15(1), 1-9.
[] [PMID: 11243375]
Wenzel, U.; Kuntz, S.; Brendel, M.D.; Daniel, H. Dietary flavone is a potent apoptosis inducer in human colon carcinoma cells. Cancer Res., 2000, 60(14), 3823-3831.
[PMID: 10919656]
Takahashi, T.; Kobori, M.; Shinmoto, H.; Tsushida, T. Structure-activity relationships of flavonoids and the induction of granulocytic- or monocytic-differentiation in HL60 human myeloid leukemia cells. Biosci. Biotechnol. Biochem., 1998, 62(11), 2199-2204.
[] [PMID: 9972240]
Marques, S.M.; Šupolíková, L.; Molčanová, L.; Šmejkal, K.; Bednar, D.; Slaninová, I. Screening of natural compounds as P-Glycoprotein inhibitors against multidrug resistance. Biomedicines, 2021, 9(4), 357.
[] [PMID: 33808505]
Jeong, H.J.; Shin, Y.G.; Kim, I.H.; Pezzuto, J.M. Inhibition of aromatase activity by flavonoids. Arch. Pharm. Res., 1999, 22(3), 309-312.
[] [PMID: 10403137]
Bandele, O.J.; Osheroff, N. Bioflavonoids as poisons of human topoisomerase II α and II β. Biochemistry, 2007, 46(20), 6097-6108.
[] [PMID: 17458941]
Ferry, D.R.; Smith, A.; Malkhandi, J.; Fyfe, D.W.; deTakats, P.G.; Anderson, D.; Baker, J.; Kerr, D.J. Phase I clinical trial of the flavonoid quercetin: Pharmacokinetics and evidence for in vivo tyrosine kinase inhibition. Clin. Cancer Res., 1996, 2(4), 659-668.
[PMID: 9816216]
Chen, Y.L.; Chen, I.L.; Tzeng, C.C.; Wang, T.C. Synthesis and cytotoxicity evaluation of certain α-methylidene-γ-butyrolactones bearing coumarin, flavone, xanthone, carbazole, and dibenzofuran moieties. Helv. Chim. Acta, 2000, 83(5), 989-994.
Cabrera, M.; Simoens, M.; Falchi, G.; Lavaggi, M.L.; Piro, O.E.; Castellano, E.E.; Vidal, A.; Azqueta, A.; Monge, A.; de Ceráin, A.L.; Sagrera, G.; Seoane, G.; Cerecetto, H.; González, M. Synthetic chalcones, flavanones, and flavones as antitumoral agents: Biological evaluation and structure–activity relationships. Bioorg. Med. Chem., 2007, 15(10), 3356-3367.
[] [PMID: 17383189]
Plochmann, K.; Korte, G.; Koutsilieri, E.; Richling, E.; Riederer, P.; Rethwilm, A.; Schreier, P.; Scheller, C. Structure–activity relationships of flavonoid-induced cytotoxicity on human leukemia cells. Arch. Biochem. Biophys., 2007, 460(1), 1-9.
[] [PMID: 17353006]
Cushman, M.; Zhu, H.; Geahlen, R.L.; Kraker, A.J. Synthesis and biochemical evaluation of a series of aminoflavones as potential inhibitors of protein-tyrosine kinases p56lck, EGFr, and p60v-src. J. Med. Chem., 1994, 37(20), 3353-3362.
[] [PMID: 7932563]
Akama, T.; Shida, Y.; Sugaya, T.; Ishida, H.; Gomi, K.; Kasai, M. Novel 5-aminoflavone derivatives as specific antitumor agents in breast cancer. J. Med. Chem., 1996, 39(18), 3461-3469.
[] [PMID: 8784443]
Akama, T.; Ishida, H.; Shida, Y.; Kimura, U.; Gomi, K.; Saito, H.; Fuse, E.; Kobayashi, S.; Yoda, N.; Kasai, M. Design and synthesis of potent antitumor 5,4′-diaminoflavone derivatives based on metabolic considerations. J. Med. Chem., 1997, 40(12), 1894-1900.
[] [PMID: 9191967]
Beutler, J.A.; Hamel, E.; Vlietinck, A.J.; Haemers, A.; Rajan, P.; Roitman, J.N.; Cardellina, J.H., II; Boyd, M.R. Structure-activity requirements for flavone cytotoxicity and binding to tubulin. J. Med. Chem., 1998, 41(13), 2333-2338.
[] [PMID: 9632366]
Patil, V.M.; Masand, N.; Verma, S.; Masand, V. Chromones: Privileged scaffold in anticancer drug discovery. Chem. Biol. Drug Des., 2021, 98(5), 943-953.
[] [PMID: 34519163]
Dyrager, C. Design and synthesis of chalcone and chromone derivatives as novel anticancer agents. PhD Thesis; University of Gothenburg: Sweden, 2012.
Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Shahar Yar, M. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem., 2017, 125, 143-189.
[] [PMID: 27662031]
Martins, P.; Jesus, J.; Santos, S.; Raposo, L.; Roma-Rodrigues, C.; Baptista, P.; Fernandes, A. Heterocyclic anticancer compounds: Recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules, 2015, 20(9), 16852-16891.
[] [PMID: 26389876]
Mečiarová, M.; Toma, Š.; Magdolen, P. Ultrasound effect on the aromatic nucleophilic substitution reactions on some haloarenes. Ultrason. Sonochem., 2003, 10(4-5), 265-270.
[] [PMID: 12818392]
Kotha, R.R.; Kulkarni, R.G.; Garige, A.K.; Nerella, S.G.; Garlapati, A. Synthesis and cytotoxic activity of new chalcones and their flavonol derivatives. Med. Chem., 2017, 7, 353-360.
Fegade, B.; Jadhav, S. Design, synthesis and molecular docking study of N-Heterocyclic chalcone derivatives as an anti-cancer agent. Int. J. Pharm. Sci. Drug Res., 2022, 14(1), 78-84.
Patel, S.; Shah, U.H. Synthesis of flavones from 2-hydroxy acetophenone and aromatic aldehyde derivatives by conventional methods and green chemistry approach. Asian J. Pharm. Clin. Res., 2017, 10(2), 403-406.
Kandeel, E.M. B.M.A.; Kandeel, E.M.; Abdel-Rahman, A.H.; Abdel-Motaal, M. Synthesis, antioxidant and cytotoxic activities of novel naphthoquinone derivatives from 2, 3-dihydro-2, 3-epoxy-1, 4-naphthoquinone. Med. Chem. (Los Angeles), 2014, 4(3), 381-388.
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.
[] [PMID: 6606682]
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82(13), 1107-1112.
[] [PMID: 2359136]
Kntayya, S.; Ibrahim, M.; Mohd Ain, N.; Iori, R.; Ioannides, C.; Abdull Razis, A. Induction of apoptosis and cytotoxicity by isothiocyanate sulforaphene in human hepatocarcinoma HepG2 cells. Nutrients, 2018, 10(6), 718.
[] [PMID: 29866995]
Bhagwat, D.A.; Swami, P.A.; Nadaf, S.J.; Choudhari, P.B.; Kumbar, V.M.; More, H.N.; Killedar, S.G.; Kawtikwar, P.S. Capsaicin loaded solid SNEDDS for enhanced bioavailability and anticancer activity: In vitro, in silico, and in vivo characterization. J. Pharm. Sci., 2021, 110(1), 280-291.
[] [PMID: 33069713]
Ibata, T.; Isogami, Y.; Toyoda, J. Aromatic nucleophilic substitution of halobenzenes with amines under high pressure. Bull. Chem. Soc. Jpn., 1991, 64(1), 42-49.
Meyer, B.; Ferrigni, N.; Putnam, J.; Jacobsen, L.; Nichols, D.; McLaughlin, J. Brine shrimp: A convenient general bioassay for active plant constituents. Planta Med., 1982, 45(5), 31-34.
[] [PMID: 17396775]
Masuda, H.; Zhang, D.; Bartholomeusz, C.; Doihara, H.; Hortobagyi, G.N.; Ueno, N.T. Role of epidermal growth factor receptor in breast cancer. Breast Cancer Res. Treat., 2012, 136(2), 331-345.
[] [PMID: 23073759]
Jeong, Y.; Bae, S.Y.; You, D.; Jung, S.P.; Choi, H.J.; Kim, I.; Lee, S.K.; Yu, J.; Kim, S.W.; Lee, J.E.; Kim, S.; Nam, S.J. EGFR is a therapeutic target in hormone receptor-positive breast cancer. Cell. Physiol. Biochem., 2019, 53(5), 805-819.
[] [PMID: 31670920]
Hu, G.; Liu, W.; Mendelsohn, J.; Ellis, L.M.; Radinsky, R.; Andreeff, M.; Deisseroth, A.B. Expression of epidermal growth factor receptor and human papillomavirus E6/E7 proteins in cervical carcinoma cells. J. Natl. Cancer Inst., 1997, 89(17), 1271-1276.
[] [PMID: 9293917]
Batran, R.Z.; Dawood, D.H.; El-Seginy, S.A.; Ali, M.M.; Maher, T.J.; Gugnani, K.S.; Rondon-Ortiz, A.N. New coumarin derivatives as anti‐Breast and anti‐cervical cancer agents targeting VEGFR2 and p38α MAPK. Arch. Pharm., 2017, 350(9), 1700064.
[] [PMID: 28787092]
Thomas, C.; Gustafsson, J.Å. The different roles of ER subtypes in cancer biology and therapy. Nat. Rev. Cancer, 2011, 11(8), 597-608.
[] [PMID: 21779010]

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