Antitumor Activity of a Quinoline-Substituted Chalcone Epoxide http://www.doi.org/10.26538/tjnpr/v7i8.30
Article Sidebar
Main Article Content
Abstract
Cancer is a multifactorial disease. Chalcones have been identified as potential antitumor agents that target tubulin. This study aims to synthesize and evaluate the antitumor activity of a quinolinesubstituted chalcone epoxide as a potential tubulin inhibitor. The compound was synthesized by Claisen-Schmidt condensation and named C1, its structure was established using various spectroscopic techniques. The median lethal dose (LD50) of C1 was evaluated using OECD 425 guidelines, antitumor activity was evaluated in 1-methyl nitrosourea (MNU)-induced mammary tumors in rats. Eight weeks post-MNU administration, the animals were divided into five groups of six rats each and treated with graded doses (12.5, 25, and 50 mg/kg) of C1 and paclitaxel (10 mg/kg) for six weeks. At the end of the treatment, the rats were euthanized, and mammary glands were collected and subjected to histological assessment to confirm tumor induction and assess treatment with C1. The possible mechanism of action of C1 was elucidated in silico using molecular docking. The LD50 of C1 was above 2000 mg/kg. There was significant decrease (p = 0.041) in mean tumor diameter when compared with the untreated group. Histological assessment shows that the lactiferous gland of the rats treated with MNU and graded doses of C1 showed fewer signs of hyperplasia with a small number of tumor cells in the duct when compared with the cancer control group. Tubulin-binding interaction revealed that C1 and Colchicine have the same binding site. These results suggest that C1 may have potential anticancer activity possibly via microtubule destabilization.
Article Details
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
References
National Comprehensive Cancer Network (NCCN). Practice guidelines in oncology: breast cancer. Version 3. [online] 2014 Available from: www.nccn.org.
World Health Organization. Cancer facts sheet. No 307” 2019.
Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistic. Cancer J. 2005; 53:74-108.
Fasoranti TO. Combating breast cancer in Nigeria; the need for comprehensive screening programs. [online] 2012 (cited 2011) available from: http://www.gamji.com/article600/News7489htm.
Nepali K, Sharma S, Sharma M, Bedi PMS, Dhar KL. Rational approaches, design strategies, structure-activity relationship and mechanistic insights for anticancer hybrids, Eur J Med Chem. 2014; 77: 422-487.
Petrelli A, Giordano S. From single- to multi-target drugs in cancer therapy: When a specificity becomes an advantage. Curr Med Chem. 2008; 15: 422-432.
Perez EA. Microtubule inhibitors: Differentiating tubulininhibiting agents based on mechanisms of action, clinical activity, and resistance. Mol Cancer Therapeutics 2009; 8: 2086.
Jordan MA, Kamath K. How do microtubule-targeted drugs work? An overview. Curr Cancer Drug Targets 2007; 7: 730.
Bhalla KN. Microtubule-targeted anticancer agents and apoptosis. Oncogene 2003; 22: 9075.
Kim JS, Lee YC, Nam HT, Li G, Yun EJ, Song KS, Seo KS, Park JH, Ahn JW, Zee O. Apicularen A induces cell death through fas ligand up-regulation and microtubule disruption by tubulin down-regulation in hm7 human colon cancer cells. Clin. Cancer Res. 2007; 13: 6509-6517.
Kavallaris M. Microtubules and resistance to tubulin-binding agents. Nat Rev Cancer 2010; 10: 194.
Lockwood AH. Molecules in the mammalian brain that interact with the colchicine site on tubulin. Proc Natl Acad Sci U S A. 1997; 76: 1184.
Lu Y, Chen J, Xiao M, Li W, Miller DD. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res. 2012; 29: 2943-2971.
Buey RM, Calvo E, Barasoain I, Pineda O, Edler MC, Matesanz R, Cerezo G, Vanderwal CD, Day BW, Sorensen EJ. Cyclostreptin binds covalently to microtubule pores and luminal taxoid binding sites. Nat Chem Biol. 2007; 3: 117.
Field JJ, Pera B, Calvo E, Canales A, Zurwerra D, Trigili C, Rodríguezsalarichs J, Matesanz R, Kanakkanthara A, Wakefield SJ. Zampanolide, a potent new microtubule stabilizing agent, covalently reacts with the taxane luminal site in both tubulin α, β-heterodimers, and microtubules.
Chem Biol 2012; 19: 686.
Prota AE, Bargsten K, Zurwerra D, Field JJ, Díaz JF, Altmann KH, Steinmetz MO. Molecular mechanism of action of microtubule-stabilizing anticancer agents. Science 2013; 339: 587.
Shan B, Medina JC, Santha E, Frankmoelle WP, Chou T, Learned RM, Narbut MR, Stott D, Wu P, Jaen JC. Selective, covalent modification of β-tubulin residue cys-239 by t138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors. Proc Natl Acad Sci U S A 1999;
: 5686-5691.
Sanat KMS. Rational drug design. Eur J Pharmacology. 2009; 90-100.
Lu Y, Chen J, Xiao M, Li W, Miller DD. An overview of tubulin inhibitors that interact with the colchicine binding site. Pharm. Res. 2012; 29: 2943-2971.
Cancino K, Castro I, Yaur C, Jullian V, Arévalo J, Sauvain M, Adaui V, Castillo D. Toxicity assessment of synthetic chalcones with antileishmanial potential in balb/C mice. Rev. Peru. Med. 2021; 38: 424-433.
Organization for Economic Cooperation and Development. OECD Guidelines for testing of chemicals, acute oral toxicity. 2001; 423: 1-14
Kluver H, Barrera E. A method for the combined staining of cells and fibers in the nervous system. J. Neuropath Exp. Neurol. 1953; 12:400-410
Thompson HJ, Adlakha H. Dose-responsive induction of mammary gland carcinomas by the intraperitoneal injection of 1-methyl-1-nitrosourea. Cancer Res. 1992; 51:3411–3415.
Towle MJ, Salvato KA, Wels BF, Aalfs KK, Zheng W, Seletsky BM, Zhu X, Lewis B. Eribulin Induces irreversible mitotic blockade: implications of cell-based pharmacodynamics for in vivo efficacy under intermittent dosing conditions. Cancer Res 2011; 71: 496-505.
Bandgar BP, Gawande SS, Bodade RG, Totre JV, Khobragade CN. Synthesis and biological evaluation of simple methoxylated chalcones as anticancer, antiinflammatory, and antioxidant agents. Bioorganic MedChem. 2010; 18: 1364-1370.
Lipinski CA. Lead-and drug-like compounds: the rule-offive revolution. Drug discovery today. Technologies. 2004; 4: 337-341.
Kumar B, Singh S, Skvortsova I, Kumar V. Promising targets in anticancer drug development: Recent updates. Curr med chem. 2007; 24: 4729-4752.
Gomes MN, Muratov EN, Pereira M, Peixoto JC, Rosseto LP, Cravo PVL, Neves BJ. Chalcone derivatives: Promising starting points for drug design. molecules. 2017; 22. doi:Doi:https://doi.org/10.3390/molecules22081210.
Zingales SK, Moore ME. Design and synthesis of (2-(furanyl)vinyl)-1-tetralone chalcones as anticancer agents. Der Pharma Chemica. 2016; 8: 40–47.
Lawrence T, Gilroy DW. Chronic inflammation: a failure of resolution? Int J Exp Pathology. 2007; 88: 85-94. doi:DOI: 10.1111/j.1365-2613.2006.00507.
Dong M, Liu F, Zhou H, Zhai S, Yan B. Novel natural product-and privileged scaffold-based tubulin inhibitors targeting the colchicine binding site. Molecules. 2016; 21. doi https://doi.org/10.3390/molecules21101375.
Ducki S. The development of chalcones as promising anticancer agents. JDID. 2007; 10: 42–46
Shan B, Medina JC, Santha E, Frankmoelle WP, Chou T, Learned RM, Narbut MR, Stott D, Wu P, Jaen JC. Selective, Covalent modification of β-tubulin residue Cys-239 by T138067, an antitumor agent with in vivo efficacy against multidrug-resistant tumors. Proc Natl Acad Sci U S A. 1999; 96: 5686-5691.
Prota AE. Molecular mechanism of action of microtubulestabilizing anticancer agents. Science. 2013; 3: 587.
Prota AE, Danel F, Bachmann F, Bargsten K, Buey RM, Pohlmann J, Steinmetz MO. The novel microtubuledestabilizing drug bal27862 binds to the colchicine site of tubulin with distinct effects on microtubule organization. Mol Biol. 2014; 462: 1848–1860. Doi https://doi.org/10.1016/j.jmb.2014.02.005.
Banerjee S, Arnst KE, Wang Y, Kumar G, Deng S, Yang L. Heterocyclic-fused pyrimidines as novel tubulin polymerization inhibitors targeting the colchicine binding site: structural basis and antitumor efficacy. Med Chem. 2018; doi: https://doi.org/10.1021/acs.jmedchem. 7b01858.