Design, Synthesis and In vitro Cytotoxicity of New 1,2,3-triazol- and Nitrostyrene Hybrids as Potent Anticancer Agents

Author(s): Zahra Tashrifi, Maryam Mohammadi-khanaposhtani, Mehdi Shafiee Ardestani, Maliheh Safavi, Kurosh Rad-Moghadam*, Morteza Mehrdad, Bagher Larijani, Mohammad Mahdavi*

Journal Name: Letters in Drug Design & Discovery

Volume 16 , Issue 2 , 2019

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Abstract:

Background: A new series of 1,2,3-triazol-nitrostyrene derivatives was designed, synthesized, and evaluated for cytotoxic activity against Hep-2 and L929 cell lines.

Methods: The synthetic procedure started from the functionalization of 4-hydroxybenzaldehyde with propargyl bromide and a subsequent click reaction to give 1,2,3-triazole derivatives. Then, the reaction of the mentioned derivatives with nitromethane led to the formation of the title compounds in excellent yields.

Results: Most of the compounds exhibited better cytotoxic activity with respect to the standard drug 5-fluorouracil. Among them, (E)-1-(3,4-dichlorobenzyl)-4-((4-(2-nitrovinyl)phenoxy)methyl)-1H- 1,2,3-triazole 6i (IC50 = 4.66 ± 1.3 µM) against the Hep-2 cell line and (E)-1-(2,3-dichlorobenzoyl)- 4-((4-(2-nitrovinyl)phenoxy)methyl)-1H-1,2,3-triazole 6g (IC50 = 5.18 ± 0.8 µM) against the L929 cell line exhibited the best cytotoxic effects.

Conclusion: Moreover, the acridine orange/ethidium bromide double staining technique showed that the most potent compounds 6i and 6g could induce apoptosis in studied cancer cell lines.

Keywords: 1, 2, 3-triazol, nitrostyrene, anticancer, apoptosis, cytotoxic, hybrid.

[1]
Kolb, H.C.; Sharpless, K.B. The growing impact of click chemistry on drug discovery. Drug Discovery. Today, 2003, 8, 1128-1137.
[2]
Whiting, M.; Muldoon, J.; Lin, Y.C.; Silverman, S.M.; Lindstrom, W.; Olson, A.J.; Kolb, H.C.; Finn, M.G.; Sharpless, K.B.; Elder, J.H.; Fokin, V.V. Inhibitors of HIV‐1 protease by using in situ click chemistry. Angew. Chem. Int. Ed., 2006, 45, 1435-1439.
[3]
Anand, A.; Naik, R.J.; Revankar, H.M.; Kulkarni, M.V.; Dixit, S.R.; Joshi, S.D. A click chemistry approach for the synthesis of mono and bis aryloxy linked coumarinyl triazoles as anti-tubercular agents. Eur. J. Med. Chem., 2015, 105, 194-207.
[4]
Garudachari, B.; Isloor, A.M.; Satyanarayana, M.N.; Fun, H.K.; Hegde, G. Click chemistry approach: Regioselective one-pot synthesis of some new 8-trifluoromethylquinoline based 1, 2, 3-triazoles as potent antimicrobial agents. Eur. J. Med. Chem., 2014, 74, 324-332.
[5]
Layek, S.; Kumari, S.; Agrahari, B.; Ganguly, R.; Pathak, D.D. Synthesis, characterization and crystal structure of a diketone based Cu (II) complex and its catalytic activity for the synthesis of 1, 2, 3-triazoles. Inorg. Chim. Acta, 2016, 453, 735-741.
[6]
Kolb, H.C.; Finn, M.G.; Sharpless, K.B. 2001. Click chemistry: Diverse chemical function from a few good reactions. Angew. Chem. Int. Ed., 2001, 40, 2004-2021.
[7]
Hou, W.; Luo, Z.; Zhang, G.; Cao, D.; Li, D.; Ruan, H.; Ruan, B.H.; Su, L.; Xu, H. Click chemistry-based synthesis and anticancer activity evaluation of novel C-14 1, 2, 3-triazole dehydroabietic acid hybrids. Eur. J. Med. Chem., 2017, 138, 1042-1052.
[8]
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.
[9]
Li, X.; Lin, Y.; Yuan, Y.; Liu, K.; Qian, X. Novel efficient anticancer agents and DNA-intercalators of 1, 2, 3-triazol-1, 8-naphthalimides: Design, synthesis, and biological activity. Tetrahedron, 2011, 67, 2299-2304.
[10]
Ma, N.; Wang, Y.; Zhao, B.X.; Ye, W.C.; Jiang, S. The application of click chemistry in the synthesis of agents with anticancer activity. Drug Des. Dev. Ther., 2015, 9, 1585.
[11]
Kuno, T.; Tsukamoto, T.; Hara, A.; Tanaka, T. Cancer chemoprevention through the induction of apoptosis by natural compounds. J. Biophys. Chem, 2012, 3, 156-173.
[12]
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, 1181-1191.
[13]
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, 3045-3049.
[14]
Kaap, S.; Quentin, I.; Tamiru, D.; Shaheen, M.; Eger, K.; Steinfelder, H.J. Structure activity analysis of the pro-apoptotic, antitumor effect of nitrostyrene adducts and related compounds. J. Biochem. Pharmacol, 2003, 65, 603-610.
[15]
Reddy, M.A.; Jain, N.; Yada, D.; Kishore, C.; Vangala, J.R.P.; Surendra, R.; Addlagatta, A.; Kalivendi, S.V.; Sreedhar, B. Design and synthesis of resveratrol-based nitrovinylstilbenes as antimitotic agents. J. Med. Chem., 2011, 54, 6751-6760.
[16]
Rahmani-Nezhad, S.; Safavi, M.; Pordeli, M.; Ardestani, S.K.; Khosravani, L.; Pourshojaei, Y.; Mahdavi, M.; Emami, S.; Foroumadi, A.; Shafiee, A. Synthesis, in vitro cytotoxicity and apoptosis inducing study of 2-aryl-3-nitro-2H-chromene derivatives as potent anti-breast cancer agents. Eur. J. Med. Chem., 2014, 86, 562-569.
[17]
Viegas-Junior, C.; Danuello, A.; da Silva Bolzani, V.; Barreiro, E.J.; Fraga, C.A.M. Molecular hybridization: A useful tool in the design of new drug prototypes. Curr. Med. Chem., 2007, 14, 1829-1852.
[18]
Mohammadi-Khanaposhtani, M.; Saeedi, M.; Zafarghandi, N.S.; Mahdavi, M.; Sabourian, R.; Razkenari, E.K.; Alinezhad, H.; Khanavi, M.; Foroumadi, A.; Shafiee, A.; Akbarzadeh, T. Potent acetylcholinesterase inhibitors: Design, synthesis, biological evaluation, and docking study of acridone linked to 1, 2, 3-triazole derivatives. Eur. J. Med. Chem., 2015, 92, 799-806.
[19]
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.
[20]
Mohammadi-Khanaposhtani, M.; Shabani, M.; Faizi, M.; Aghaei, I.; Jahani, R.; Sharafi, Z.; Zafarghandi, N.S.; Mahdavi, M.; Akbarzadeh, T.; Emami, S.; Shafiee, 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.
[21]
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.
[22]
Najafi, Z.; Mahdavi, M.; Saeedi, M.; Sabourian, R.; Khanavi, M.; Safavi, M.; Tehrani, M.B.; Shafiee, A.; Foroumadi, A.; Akbarzadeh, T. 1, 2, 3-Triazole-isoxazole based acetylcholinesterase inhibitors: Synthesis, biological evaluation and docking study. Lett. Drug Des. Discov., 2017, 14, 58-65.
[23]
Vafadarnejad, F.; Saeedi, M.; Mahdavi, M.; Rafinejad, A.; Karimpour-Razkenari, E.; Sameem, B.; Khanavi, M.; Akbarzadeh, T. Novel indole-isoxazole hybrids: Synthesis and in vitro anti-cholinesterase activity. Lett. Drug Des. Discov., 2017, 14, 712-717.
[24]
Jiang, Y.; Kong, D.; Zhao, J.; Zhang, W.; Xu, W.; Li, W.; Xu, G. A simple, efficient thermally promoted protocol for Huisgen-click reaction catalyzed by CuSO4·5H2O in water. Tetrahed Lett., 2014, 55, 2410-2414.
[25]
Hans, R.H.; Guantai, E.M.; Lategan, C.; Smith, P.J.; Wan, B.; Franzblau, S.G.; Gut, J.; Rosenthal, P.J.; Chibale, K. Synthesis, antimalarial and antitubercular activity of acetylenic chalcones. Bioorg. Med. Chem. Lett., 2010, 20, 942-944.
[26]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: Application to proliferation and cytotoxicity assays. J. Immunol. Meth, 1983, 65, 55-63.
[27]
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, 12.


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Article Details

VOLUME: 16
ISSUE: 2
Year: 2019
Page: [213 - 219]
Pages: 7
DOI: 10.2174/1570180815666180427151830
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