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Anti-Cancer Agents in Medicinal Chemistry


ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

General Research Article

Design, Synthesis, In vitro Cytotoxic Activity Evaluation, and Study of Apoptosis Inducing Effect of New Styrylimidazo[1,2-a]Pyridines as Potent Anti-Breast Cancer Agents

Author(s): Faeze Khalili, Sara Akrami, Malihe Safavi, Maryam Mohammadi-Khanaposhtani, Mina Saeedi, Sussan K. Ardestani, Bagher Larijani, Afsaneh Zonouzi*, Maliheh B. Tehrani* and Mohammad Mahdavi*

Volume 19, Issue 2, 2019

Page: [265 - 275] Pages: 11

DOI: 10.2174/1871520618666180903100835

Price: $65


Background: This paper reports synthesis, cytotoxic activity, and apoptosis inducing effect of a novel series of styrylimidazo[1,2-a]pyridine derivatives.

Objective: In this study, anti-cancer activity of novel styrylimidazo[1,2-a]pyridines was evaluated.

Methods: Styrylimidazo[1,2-a]pyridine derivatives 4a-o were synthesized through a one-pot three-component reaction of 2-aminopyridines, cinnamaldehydes, and isocyanides in high yield. All synthesized compounds 4a-o were evaluated against breast cancer cell lines including MDA-MB-231, MCF-7, and T-47D using MTT assay. Apoptosis was evaluated by acridine orange/ethidium bromide staining, cell cycle analysis, and TUNEL assay as the mechanism of cell death.

Results: Most of the synthesized compounds exhibited more potent cytotoxicity than standard drug, etoposide. Induction of apoptosis by the most cytotoxic compounds 4f, 4g, 4j, 4n, and 4m was confirmed through mentioned methods.

Conclusion: In conclusion, these results confirmed the potency of styrylimidazo[1,2-a]pyridines for further drug discovery developments in the field of anti-cancer agents.

Keywords: Anti-cancer, apoptosis, cytotoxicity, styrylimidazo[1, 2-a]pyridines, TUNEL assay, anti-breast cancer.

Graphical Abstract
Murray, C.J.; Lopez, A.D. and World Health Organization. The global burden of disease: A comprehensive assessment of mortality and disability from diseases, injuries, and risk factors in 1990 and projected to 2020: summary. 1996.
Landis, S.H.; Murray, T.; Bolden, S.; Wingo, P.A. Cancer statistics, 1999, Cancer. J. Clin., 1999, 49(1), 8-31.
Perez-Tomas, R. Multidrug resistance: Retrospect and prospects in anti-cancer drug treatment. Curr. Med. Chem., 2006, 13(16), 1859-1876.
Kuno, T.; Tsukamoto, T.; Hara, A.; Tanaka, T. Cancer chemoprevention through the induction of apoptosis by natural compounds. J. Biophys. Chem., 2012, 3(2), 156.
Chou, C.C.; Yang, J.S.; Lu, H.F.; Ip, S.W.; Lo, C.; Wu, C.C.; Lin, J.P.; Tang, N.Y.; Chung, J.G.; Chou, M.J.; Teng, Y.H. Quercetin-mediated cell cycle arrest and apoptosis involving activation of a caspase cascade through the mitochondrial pathway in human breast cancer MCF-7 cells. Arch. Pharm. Res., 2010, 33(8), 1181-1191.
Kemnitzer, W.; Kuemmerle, J.; Jiang, S.; Zhang, H.Z.; Sirisoma, N.; Kasibhatla, S.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery of 1-benzoyl-3-cyanopyrrolo [1, 2-a] quinolines as a new series of apoptosis inducers using a cell-and caspase-based high-throughput screening assay. Part 1: Structure–activity relationships of the 1-and 3-positions. Bioorg. Med. Chem. Lett., 2008, 18(23), 6259-6264.
Kemnitzer, W.; Sirisoma, N.; Nguyen, B.; Jiang, S.; Kasibhatla, S.; Crogan-Grundy, C.; Tseng, B.; Drewe, J.; Cai, S.X. Discovery of N-aryl-9-oxo-9H-fluorene-1-carboxamides as a new series of apoptosis inducers using a cell-and caspase-based high-throughput screening assay. 1. Structure–activity relationships of the carboxamide group. Bioorg. Med. Chem. Lett., 2009, 19(11), 3045-3049.
Goldar, S.; Khaniani, M.S.; Derakhshan, S.M.; Baradaran, B. Molecular mechanisms of apoptosis and roles in cancer development and treatment. Asian Pac. J. Cancer Prev., 2015, 16(6), 2129-2144.
De-Filippis, B. Anticancer activity of stilbene‐based derivatives. ChemMedChem, 2017, 12(8), 558-570.
Martí-Centelles, R.; Murga, J.; Falomir, E.; Carda, M.; Marco, J.A. Inhibitory effect of cytotoxic nitrogen-containing heterocyclic stilbene analogues on VEGF protein secretion and VEGF, hTERT and c-Myc gene expression. MedChemComm, 2015, 6(10), 1809-1815.
Trapani, G.; Franco, M.; Latrofa, A.; Ricciardi, L.; Carotti, A.; Serra, M.; Sanna, E.; Biggio, G.; Liso, G. Novel 2-phenylimidazo [1, 2-a] pyridine derivatives as potent and selective ligands for peripheral benzodiazepine receptors: Synthesis, binding affinity, and in vivo studies. J. Med. Chem., 1999, 42(19), 3934-3941.
Almirante, L.; Polo, L.; Mugnaini, A.; Provinciali, E.; Rugarli, P.; Biancotti, A.; Gamba, A.; Murmann, W. Derivatives of imidazole. I. Synthesis and reactions of imidazo [1, 2-α] pyridines with analgesic, antiinflammatory, antipyretic, and anticonvulsant activity. J. Med. Chem., 1965, 8(3), 305-312.
Couty, F.; Evano, G. Chapter 10, in: Katritzky, A.R.; Ramsden, C.A.; Scriven, E.V.F.; Taylor, R.J.K. (Eds.). Comprehensive Heterocyclic Chemistry III,, Elsevier Science, Oxford. 2008, 11, 409- 492.
Rupert, K.C.; Henry, J.R.; Dodd, J.H.; Wadsworth, S.A.; Cavender, D.E.; Olini, G.C.; Fahmy, B.; Siekierka, J.J. Imidazopyrimidines, potent inhibitors of p38 MAP kinase. Bioorg. Med. Chem. Lett., 2003, 13(3), 347-350.
Baviskar, A.T.; Madaan, C.; Preet, R.; Mohapatra, P.; Jain, V.; Agarwal, A.; Guchhait, S.K.; Kundu, C.N.; Banerjee, U.C.; Bharatam, P.V. N-fused imidazoles as novel anticancer agents that inhibit catalytic activity of topoisomerase IIα and induce apoptosis in G1/S phase. J. Med. Chem., 2011, 54(14), 5013-5030.
Nikookar, H.; Mohammadi-Khanaposhtani, M.; Imanparast, S.; Faramarzi, M.A.; Ranjbar, P.R.; Mahdavi, M.; Larijani, B. Design, synthesis and in vitro α-glucosidase inhibition of novel dihydropyrano [3, 2-c] quinoline derivatives as potential anti-diabetic agents. Bioorg. Chem., 2018, 77, 280-286.
Arab, S.; Sadat‐Ebrahimi, S.E.; Mohammadi‐Khanaposhtani, M.; Moradi, A.; Nadri, H.; Mahdavi, M.; Moghimi, S.; Asadi, M.; Firoozpour, L.; Pirali‐Hamedani, M.; Shafiee, A. Synthesis and evaluation of chroman‐4‐one linked to n‐benzyl pyridinium derivatives as new acetylcholinesterase inhibitors. Arch. Pharm., 2015, 348, 643-649.
Mohammadi‐Khanaposhtani, M.; Mahdavi, M.; Saeedi, M.; Sabourian, R.; Safavi, M.; Khanavi, M.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Design, synthesis, biological evaluation, and docking study of acetylcholinesterase inhibitors: New acridone‐1, 2, 4‐oxadiazole‐1, 2, 3‐triazole hybrids. Chem. Biol. Drug Des., 2015, 86, 1425-1432.
Mohammadi-Khanaposhtani, M.; Safavi, M.; Sabourian, R.; Mahdavi, M.; Pordeli, M.; Saeedi, M.; Ardestani, S.K.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Design, synthesis, in vitro cytotoxic activity evaluation, and apoptosis-induction study of new 9 (10H)-acridinone-1, 2, 3-triazoles. Mol. Divers., 2015, 19, 787-795.
Mohammadi-Khanaposhtani, M.; Shabani, M.; Faizi, M.; Aghaei, I.; Jahani, R.; Sharafi, Z.; Zafarghandi, N.S.; Mahdavi, M.; Akbarzadeh, T.; Emami, S.; Shafiee, A.; Foroumadi, A. Design, synthesis, pharmacological evaluation, and docking study of new acridone-based 1, 2, 4-oxadiazoles as potential anticonvulsant agents. Eur. J. Med. Chem., 2016, 112, 91-98.
Rahmani-Nezhad, S.; Khosravani, L.; Saeedi, M.; Divsalar, K.; Firoozpour, L.; Pourshojaei, Y.; Sarrafi, Y.; Nadri, H.; Moradi, A.; Mahdavi, M.; Shafiee, A. Synthesis and evaluation of coumarin–resveratrol hybrids as 15-lipoxygenaze inhibitors. Synth. Commun., 2015, 45(6), 741-749.
Mehrabi, F.; Pourshojaei, Y.; Moradi, A.; Sharifzadeh, M.; Khosravani, L.; Sabourian, R.; Rahmani-Nezhad, S.; Mohammadi-Khanaposhtani, M.; Mahdavi, M.; Asadipour, A.; Rahimi, H.R. Design, synthesis, molecular modeling and anticholinesterase activity of benzylidene-benzofuran-3-ones containing cyclic amine side chain. Future Med. Chem., 2017, 9(7), 659-671.
Akbarzadeh, T.; Ebrahimi, A.; Saeedi, M.; Mahdavi, M.; Foroumadi, A.; Shafiee, A. Synthesis of novel 5-phenylimidazo [1,2-c] quinazolin-3-amine derivatives via Groebke–blackburn-bienaymé multicomponent reaction. Monatsh. Chem., 2014, 145(9), 1483-1487.
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65, 55-63.
Kelm, J.M.; Timmins, N.E.; Brown, C.J.; Fussenegger, M.; Nielsen, L.K. Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol. Bioeng., 2003, 83(2), 173-180.
Foty, R. A simple hanging drop cell culture protocol for generation of 3D spheroids. J. Vis. Exp., 2011, 51, 2720.
Breslin, S.; O’Driscoll, L. Three-dimensional cell culture: the missing link in drug discovery. Drug Discov. Today, 2013, 18(5-6), 240-249.
Ho, W.Y.; Yeap, S.K.; Ho, C.L.; Rahim, R.A.; Alitheen, N.B. Development of Multicellular Tumor Spheroid (MCTS) culture from breast cancer cell and a high throughput screening method using the MTT assay. PLoS One, 2012, 7(9), 44640.
Ribble, D.; Goldstein, N.B.; Norris, D.A.; Shellman, Y.G. A simple technique for quantifying apoptosis in 96-well plates. BMC Biotechnol., 2005, 5(1), 12.
Safavi, M.; Esmati, N.; Ardestani, S.K.; Emami, S.; Ajdari, S.; Davoodi, J.; Shafiee, A.; Foroumadi, A. Halogenated flavanones as potential apoptosis-inducing agents: Synthesis and biological activity evaluation. Eur. J. Med. Chem., 2012, 58, 573-580.
Sun, J.; Zhang, X.; Broderick, M.; Fein, H. Measurement of nitric oxide production in biological systems by using Griess reaction assay. Sensors., 2003, 3(8), 276-284.
LeBel, C.P.; Ischiropoulos, H.; Bondy, S.C. Evaluation of the probe 2′, 7′-dichlorofluorescin as an indicator of reactive oxygen species formation and oxidative stress. Chem. Res. Toxicol., 1992, 5(2), 227-231.

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