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
Research Article

Design, Synthesis and Bioactivity Evaluation of Novel Chalcone Derivatives Possessing Tryptophan Moiety with Dual Activities of Anti-Cancer and Partially Restoring the Proliferation of Normal Kidney Cells Pre-Treated with Cisplatin

Author(s): Meng He, Mingjun Yu, Chao Li, Xiaoming Meng, Jiamin Su, Yuting Zhu and Risheng Yao*

Volume 22, Issue 10, 2022

Published on: 12 January, 2022

Page: [1945 - 1961] Pages: 17

DOI: 10.2174/1871520621666211021134626

Price: $65

Abstract

Background: Chalcone is a broad-spectrum natural product with anti-cancer and anti-inflammatory activities. However, low potency, low selectivity, and serious side effects limit its druggability. L-Tryptophan is an essential precursor molecule of an anti-cancer active substance. Also, the indole moiety inhibits the proliferation of tumor cells by binding to colchicine sites. A decrease in kidney cell activity caused by kidney inflammation is the primary side effect of cancer therapy.

Objective: The purpose of this work was to design, synthesize, and perform bioactivity evaluation of novel chalcone derivatives possessing tryptophan moiety with dual activities of anti-cancer and partially restoring the proliferation of normal kidney cells pre-treated with cisplatin.

Methods: A series of novel chalcone derivatives possessing tryptophan moiety (5a-5g, 6a-6o) were designed, synthesized, and evaluated for anti-cancer activity against four cancer cell lines (gastric (HGC-27), colon (HCT-116), prostate (PC-3), and lung (A549)), and a human normal cell line (gastric mucosal epithelial (GES-1)). The activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin was evaluated by MTT assay. Cell cycle, apoptosis, and apoptosis proteins (Bax and Bcl-2) were used to evaluate the anti-cancer mechanism of the most potent compound. Moreover, a docking study was performed to explain the high anti-cancer activity of 6n. The expressions of TNF-α, IL- 6, and MCP-1 were detected by ELISA.

Results: Most of the compounds exhibited high anti-cancer activity against the HGC-27 cell line and exhibited low toxicity against the normal cell line. Based on three rounds of a structure optimization, 6n was discovered as the most potent compound against HGC-27 cells with an IC50 value of 2.02 μM and an SI value of 28.47. Further studies demonstrated that 6n could induce cell cycle arrest at the G2/M phase and the apoptosis of the HGC-27 cell line by reducing the expression of Bcl-2 and improving the expression level of Bax. Molecular docking result displayed 6n bound to the colchicine site. At the same time, 6n also exhibited moderate activity of restoring the proliferation of normal kidney cells pre-treated with cisplatin by reducing the expression of inflammatory substances.

Conclusion: Our findings collectively suggested that 6n should be further studied as a potential anti-cancer agent that could partially restore the proliferation of normal kidney cells pre-treated with cisplatin in gastric cancer patients by an anti-inflammatory pathway.

Keywords: Chalcones, L-tryptophan, anti-cancer, colchicine, nephrotoxicity, HGC-27 cells, HK-2 cells.

« Previous Next »
Graphical Abstract

[1]
Lim, Y.H.; Oo, C.W.; Koh, R.Y.; Voon, G.L.; Yew, M.Y.; Yam, M.F.; Loh, Y.C. Synthesis, characterization, and anti-cancer activity of new chalcone derivatives containing naphthalene and fluorine moieties. Drug Dev. Res., 2020, 81(8), 994-1003.
[http://dx.doi.org/10.1002/ddr.21715] [PMID: 32720715]
[2]
Mahapatra, D.K.; Bharti, S.K.; Asati, V. Anti-cancer chalcones: Structural and molecular target perspectives. Eur. J. Med. Chem., 2015, 98(32), 69-114.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.004] [PMID: 26005917]
[3]
Ravelli, R.B.G.; Gigant, B.; Curmi, P.A.; Jourdain, I.; Lachkar, S.; Sobel, A.; Knossow, M. Insight into tubulin regulation from a complex with colchicine and a stathmin-like domain. Nature, 2004, 428(6979), 198-202.
[http://dx.doi.org/10.1038/nature02393] [PMID: 15014504]
[4]
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]
[5]
Yao, S.; Wei, B.; Yu, M.; Meng, X.; He, M.; Yao, R. Design, synthesis and evaluation of PD176252 analogues for ameliorating cisplatin-induced nephrotoxicity. MedChemComm, 2019, 10(5), 757-763.
[http://dx.doi.org/10.1039/C8MD00632F] [PMID: 31191866]
[6]
Wang, D.; Liang, J.; Zhang, J.; Wang, Y.; Chai, X. Natural chalcones in Chinese materia medica. Licorice. Evid. Based Complement. Alternat. Med., 2020, 2020(6)3821248
[http://dx.doi.org/10.1155/2020/3821248] [PMID: 32256642]
[7]
Akihisa, T.; Tokuda, H.; Ukiya, M.; Iizuka, M.; Schneider, S.; Ogasawara, K.; Mukainaka, T.; Iwatsuki, K.; Suzuki, T.; Nishino, H. Chalcones, coumarins, and flavanones from the exudate of Angelica keiskei and their chemopreventive effects. Cancer Lett., 2003, 201(2), 133-137.
[http://dx.doi.org/10.1016/S0304-3835(03)00466-X] [PMID: 14607326]
[8]
Inamori, Y.; Baba, K.; Tsujibo, H.; Taniguchi, M.; Nakata, K.; Kozawa, M. Antibacterial activity of two chalcones, xanthoangelol and 4-hydroxyderricin, isolated from the root of Angelica keiskei KOIDZUMI. Chem. Pharm. Bull. (Tokyo), 1991, 39(6), 1604-1605.
[http://dx.doi.org/10.1248/cpb.39.1604] [PMID: 1934181]
[9]
Kazmi, M.; Khan, I.; Khan, A.; Halim, S.A.; Saeed, A.; Mehsud, S.; Al-Harrasi, A.; Ibrar, A. Developing new hybrid scaffold for urease inhibition based on carbazole-chalcone conjugates: Synthesis, assessment of therapeutic potential and computational docking analysis. Bioorg. Med. Chem., 2019, 27(22)115123
[http://dx.doi.org/10.1016/j.bmc.2019.115123] [PMID: 31623971]
[10]
Nowakowska, Z. A review of anti-infective and anti-inflammatory chalcones. Eur. J. Med. Chem., 2007, 42(2), 125-137.
[http://dx.doi.org/10.1016/j.ejmech.2006.09.019] [PMID: 17112640]
[11]
Shi, M.; Zeng, X.; Guo, F.; Huang, R.; Feng, Y.; Ma, L.; Zhou, L.; Fu, P. Anti-Inflammatory pyranochalcone derivative attenuates LPS-induced acute kidney injury via inhibiting TLR4/NF-KB pathway. Molecules, 2017, 22(10), 1683.
[http://dx.doi.org/10.3390/molecules22101683]
[12]
Sabina, X.J.; Karthikeyan, J.; Velmurugan, G.; Tamizh, M.M.; Shetty, A.N. Design and in vitro biological evaluation of substituted chalcones synthesized from nitrogen mustards as potent microtubule targeted anticancer agents. New J. Chem., 2017, 41(10), 4096-4109.
[http://dx.doi.org/10.1039/C7NJ00265C]
[13]
Jandial, D.D.; Krill, L.S.; Chen, L.; Wu, C.; Ke, Y.; Xie, J.; Hoang, B.H.; Zi, X. Induction of G2M arrest by flavokawain A, a kava chalcone, increases the responsiveness of HER2-overexpressing breast cancer cells to herceptin. Molecules, 2017, 22(3), 462.
[http://dx.doi.org/10.3390/molecules22030462] [PMID: 28335434]
[14]
Kumar, S.K.; Hager, E.; Pettit, C.; Gurulingappa, H.; Davidson, N.E.; Khan, S.R. Design, synthesis, and evaluation of novel boronic-chalcone derivatives as antitumor agents. J. Med. Chem., 2003, 46(14), 2813-2815.
[http://dx.doi.org/10.1021/jm030213+] [PMID: 12825923]
[15]
Park, E.J.; Park, H.R.; Lee, J.S.; Kim, J.; Licochalcone, A. Licochalcone A: an inducer of cell differentiation and cytotoxic agent from Pogostemon cablin. Planta Med., 1998, 64(5), 464-466.
[http://dx.doi.org/10.1055/s-2006-957485] [PMID: 9690352]
[16]
Huang, X.; Liu, Z.; Wang, M.; Yin, X.; Wang, Y.; Dai, L.; Wang, H. Platinum(IV) complexes conjugated with chalcone analogs as dual targeting anticancer agents: In vitro and in vivo studies. Bioorg. Chem., 2020, 105104430
[http://dx.doi.org/10.1016/j.bioorg.2020.104430] [PMID: 33171407]
[17]
Yu, S.J.; Cho, I.A.; Kang, K.R.; Jung, Y.R.; Cho, S.S.; Yoon, G.; Oh, J.S.; You, J.S.; Seo, Y.S.; Lee, G.J.; Lee, S.Y.; Kim, D.K.; Kim, C.S.; Kim, S.G.; Jeong, M.A.; Kim, J.S. Licochalcone-E induces caspase-dependent death of human pharyngeal squamous carcinoma cells through the extrinsic and intrinsic apoptotic signaling pathways. Oncol. Lett., 2017, 13(5), 3662-3668.
[http://dx.doi.org/10.3892/ol.2017.5865] [PMID: 28521469]
[18]
Xiao, X.Y.; Hao, M.; Yang, X.Y.; Ba, Q.; Li, M.; Ni, S.J.; Wang, L.S.; Du, X.; Licochalcone, A. Licochalcone A inhibits growth of gastric cancer cells by arresting cell cycle progression and inducing apoptosis. Cancer Lett., 2011, 302(1), 69-75.
[http://dx.doi.org/10.1016/j.canlet.2010.12.016] [PMID: 21216524]
[19]
Kwak, A.W.; Choi, J.S.; Lee, M.H.; Oh, H.N.; Cho, S.S.; Yoon, G.; Liu, K.; Chae, J.I.; Shim, J.H. Retrochalcone echinatin triggers apoptosis of esophageal squamous cell carcinoma via ROS- and ER stress-mediated signaling pathways. Molecules, 2019, 24(22), 4055.
[http://dx.doi.org/10.3390/molecules24224055] [PMID: 31717502]
[20]
Dy, G.K.; Adjei, A.A. Understanding, recognizing, and managing toxicities of targeted anticancer therapies. CA Cancer J. Clin., 2013, 63(4), 249-279.
[http://dx.doi.org/10.3322/caac.21184] [PMID: 23716430]
[21]
Ruan, B.F.; Lu, X.; Tang, J.F.; Wei, Y.; Wang, X.L.; Zhang, Y.B.; Wang, L.S.; Zhu, H.L. Synthesis, biological evaluation, and molecular docking studies of resveratrol derivatives possessing chalcone moiety as potential antitubulin agents. Bioorg. Med. Chem., 2011, 19(8), 2688-2695.
[http://dx.doi.org/10.1016/j.bmc.2011.03.001] [PMID: 21440448]
[22]
Hua, S.; Chen, F.; Gou, S. Microtubule inhibitors containing immunostimulatory agents promote cancer immunochemotherapy by inhibiting tubulin polymerization and tryptophan-2,3-dioxygenase. Eur. J. Med. Chem., 2020, 187111949
[http://dx.doi.org/10.1016/j.ejmech.2019.111949] [PMID: 31830637]
[23]
Wu, K.K.; Cheng, H.H.; Chang, T.C. 5-Methoxyindole metabolites of L-tryptophan: Control of COX-2 expression, inflammation and tumorigenesis. J. Biomedence, 2014, 21(1), 17.
[http://dx.doi.org/10.1186/1423-0127-21-17]
[24]
Herkert, E.E.; Keup, W. Excretion patterns of tryptamine, indoleacetic acid, and 5-hydroxyindoleacetic acid, and their correlation with mental changes in schizophrenic patients under medication with alpha-methyldopa. Psychopharmacology (Berl.), 1969, 15(1), 48-59.
[http://dx.doi.org/10.1007/BF00410800] [PMID: 5367444]
[25]
Han, Y.; Dong, W.; Guo, Q.; Li, X.; Huang, L. The importance of indole and azaindole scaffold in the development of antitumor agents. Eur. J. Med. Chem., 2020, 203112506
[http://dx.doi.org/10.1016/j.ejmech.2020.112506] [PMID: 32688198]
[26]
Jia, Y.; Wen, X.; Gong, Y.; Wang, X. Current scenario of indole derivatives with potential anti-drug-resistant cancer activity. Eur. J. Med. Chem., 2020, 200112359
[http://dx.doi.org/10.1016/j.ejmech.2020.112359] [PMID: 32531682]
[27]
Dixit, A.; Pathak, D.; Sharma, G. A review on docking studies of indole moiety as potent inhibitor of tubulin polymerization. Eur. Chem. Bull., 2016, 5(11), 465-469.
[http://dx.doi.org/10.17628/ECB.2016.5.465]
[28]
Budama-Kilinc, Y.; Kecel-Gunduz, S.; Ozdemir, B.; Bicak, B.; Akman, G.; Arvas, B.; Aydogan, F.; Yolacan, C. New nanodrug design for cancer therapy: Its synthesis, formulation, in vitro and in silico evaluations. Arch. Pharm. (Weinheim), 2020, 353(11)e2000137
[http://dx.doi.org/10.1002/ardp.202000137] [PMID: 32757360]
[29]
Córdova-Rivas, S.; Araujo-Huitrado, J.G.; Rivera-Avalos, E.; Escalante-García, I.L.; Durón-Torres, S.M.; López-Hernández, Y.; Hernández-López, H.; López, L.; de Loera, D.; López, J.A. Differential proliferation effect of the newly synthesized valine, tyrosine and tryptophan-naphthoquinones in immortal and tumorigenic cervical cell lines. Molecules, 2020, 25(9), 2058.
[http://dx.doi.org/10.3390/molecules25092058] [PMID: 32354078]
[30]
Li, X.; Wu, J.; Li, X.; Mu, W.; Liu, X.; Jin, Y.; Xu, W.; Zhang, Y. Development of N-hydroxybenzamide derivatives with indole-containing cap group as histone deacetylases inhibitors. Bioorg. Med. Chem., 2015, 23(19), 6258-6270.
[http://dx.doi.org/10.1016/j.bmc.2015.08.040] [PMID: 26349626]
[31]
Moody, T.W.; Leyton, J.; Garcia-Marin, L.; Jensen, R.T. Nonpeptide gastrin releasing peptide receptor antagonists inhibit the proliferation of lung cancer cells. Eur. J. Pharmacol., 2003, 474(1), 21-29.
[http://dx.doi.org/10.1016/S0014-2999(03)01996-4] [PMID: 12909192]
[32]
Yu, M.J.; Yao, S.; Li, T.T.; Yang, R.; Yao, R.S. Dual anti-cancer and anti-itch activity of PD176252 analogues: Design, synthesis and biological evaluation. Anticancer. Agents Med. Chem., 2019, 19(8), 992-1001.
[http://dx.doi.org/10.2174/1871520619666190408133141] [PMID: 30961511]
[33]
Aryapour, H.; Riazi, G.H.; Ahmadian, S.; Foroumadi, A.; Mahdavi, M.; Emami, S. Induction of apoptosis through tubulin inhibition in human cancer cells by new chromene-based chalcones. Pharm. Biol., 2012, 50(12), 1551-1560.
[http://dx.doi.org/10.3109/13880209.2012.695799] [PMID: 22984888]
[34]
Li, W.; Xu, F.; Shuai, W.; Sun, H.; Yao, H.; Ma, C.; Xu, S.; Yao, H.; Zhu, Z.; Yang, D.H.; Chen, Z.S.; Xu, J. Discovery of novel quinoline-chalcone derivatives as potent antitumor agents with microtubule polymerization inhibitory activity. J. Med. Chem., 2019, 62(2), 993-1013.
[http://dx.doi.org/10.1021/acs.jmedchem.8b01755] [PMID: 30525584]

Rights & Permissions Print Cite
Article Metrics
22
1
© 2024 Bentham Science Publishers | Privacy Policy