Design, Synthesis and Anticancer Evaluation of Novel Series of Indibulin Analogues

Author(s): Ebrahim S. Moghadam, Farhad Saravani, Seyednasser Ostad, Shohreh Tavajohi, Morteza P. Hamedani, Mohsen Amini*.

Journal Name: Medicinal Chemistry

Volume 15 , Issue 3 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Abstract:

Background: Cancer is an important cause of human death worldwide. During the last decades, many anticancer agents with anti-tubulin mechanism have been synthesized or extracted from nature and some of them also entered clinical use. Indibulin is one of the most potent tubulin polymerization inhibitors with minimal peripheral neuropathy, which is a big problem by some of the antimitotic agents such as taxanes and vinka alkaloids. With respect to this giant benefit, herein we decided to design and synthesize novel indibulin related compounds and investigate their anticancer activity against HT-29, Caco-2 and T47-D cancerous cell lines as well as NIH-T3T as normal cell line.

Objective: The aim of this study was to synthesize new anti-cancer agents and evaluates their cytotoxic activity on diverse cancerous and normal cell lines.

Method: Target compounds were synthesized in multistep reaction and cytotoxic activity was investigated by MTT cell viability assay.

Results: Herein, nine novel target compounds were synthesized in moderate to good yield. Some of the compounds exerted good cytotoxic activity against cancerous cell lines. Annexin V/PI staining showed that compound 4g could induce apoptosis and necrosis in HT-29 cell line.

Conclusion: It is valuable to do further investigation on compound 4g which showed the highest activity against HT-29 and Caco-2 (IC50 values are 6.9 and 7 µM respectively). Also, synthesis of new derivatives of current synthesized compounds is suggested.

Keywords: Indibulin, anti-cancer, synthesis, apoptosis, pyrrole, MTT.

[1]
Prakasham, A.P.; Saxena, A.K.; Luqman, S.; Chanda, D.; Kaur, T.; Gupta, A.; Yadav, D.K.; Chanotiya, C.S.; Shanker, K.; Khan, F.; Negi, A.S. Synthesis and anticancer activity of 2-benzylidene indanones through inhibiting tubulin polymerization. Bioorg. Med. Chem., 2012, 20(9), 3049-3057.
[2]
Qu, S.; Mulamoottil, V.A.; Nayak, A.; Ryu, S.; Hou, X.; Song, J.; Yu, J.; Sahu, P.K.; Zhao, L.X.; Choi, S.; Lee, S.K.; Jeong, L.S. Design, synthesis and anticancer activity of C8-substituted-4′-thionucleosides as potential HSP 90 inhibitors. Bioorg. Med. Chem., 2016, 24(16), 3418-3428.
[3]
Vilanova, C.; Díaz-Oltra, S.; Murga, J.; Falomir, E.; Carda, M.; Redondo-Horcajo, M.; Díaz, J.F.; Barasoain, I.; Marco, J.A. Design and synthesis of pironetin analogue/colchicine hybrids and study of their cytotoxic activity and mechanisms of interaction with tubulin. J. Med. Chem., 2014, 57(24), 10391-10403.
[4]
Baytas, S.N.; Inceler, N.; Yilmaz, A.; Olgac, A.; Menevse, S.; Banoglu, E.; Hamel, E.; Bortolozzi, R.; Viola, G. Synthesis, biological evaluation and molecular docking studies of trans-indole-3-acrylamide derivatives, a new class of tubulin polymerization inhibitors. Bioorg. Med. Chem., 2014, 22(12), 3096-3104.
[5]
Xie, M.; Lapidus, R.G.; Sadowska, M.; Edelman, M.J.; Hosmane, R.S. Synthesis, anticancer activity, and SAR analyses of compounds containing the 5:7-fused 4,6,8-triaminoimidazo [4,5-e] [1,3] diazepine ring system. Bioorg. Med. Chem., 2016, 24(12), 2595-2602.
[6]
Siegel, R.L.; Miller, K.D.; Jemal, A. Cancer statistics, 2017. CA Cancer J. Clin., 2017, 67, 7-30.
[7]
Perreault, M.; Maltais, R.; Roy, J.; Dutour, R.; Poirier, D. Design of a mestranol 2-N-piperazino-substituted derivative showing potent and selective in vitro and in vivo activities in MCF-7 breast cancer models. ChemMedChem, 2017, 12, 177-182.
[8]
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-2Hchromene derivatives as potent anti-breast cancer agents. Eur. J. Med. Chem., 2014, 86, 562-569.
[9]
Xiao, M.; Ahn, S.; Wang, J.; Chen, J.; Miller, D.D.; Dalton, J.T.; Li, W. Discovery of 4-aryl-2-benzoyl-imidazoles as tubulin polymerization inhibitor with potent antiproliferative properties. J. Med. Chem., 2013, 56, 3318-3329.
[10]
Yin, Y.; Qiao, F.; Jiang, L.Y.; Wang, S.F.; Sha, S.; Wu, X.; Lv, P.C.; Zhu, H.L. Design, synthesis and biological evaluation of (E)-3-(3,4-dihydroxyphenyl) acrylylpiperazine derivatives as a new class of tubulin polymerization inhibitors. Bioorg. Med. Chem., 2014, 22, 4285-4292.
[11]
Zhao, L.; Mao, L.; Hong, G.; Yang, X.; Liu, T. Design, synthesis and anticancer activity of matrine–1H-1,2,3-triazole–chalcone conjugates. Bioorg. Med. Chem. Lett., 2015, 25, 2540-2544.
[12]
Mahdavi, M.; Pedrood, K.; Safavi, M.; Saeedi, M.; Pordeli, M.; Ardestani, S.K.; Emami, S.; Adib, M.; Foroumadi, A.; Shafiee, A. Synthesis and anticancer activity of N-substituted 2- arylquinazolinones bearing trans-stilbene scaffold. Eur. J. Med. Chem., 2015, 95, 492-499.
[13]
Romagnoli, R.; Baraldi, P.G.; Salvador, M.K.; Preti, D.; Tabrizi, M.A.; Brancale, A.; Fu, X.H.; Li, J.; Zhang, S.Z.; Hamel, E.; Bortolozzi, R.; Basso, G.; Viola, G. Synthesis and evaluation of 1,5-disubstituted tetrazoles as rigid analogues of combretastatin A-4 with potent antiproliferative and antitumor activity. J. Med. Chem., 2012, 55, 475-488.
[14]
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, 2943-2971.
[15]
Wienecke, A.; Bacher, G. Indibulin, a novel microtubule inhibitor, discriminates between mature neuronal and nonneuronal tubulin. Cancer Res., 2009, 69, 171-177.
[16]
Colley, H.E.; Muthana, M.; Danson, S.J.; Jackson, L.V.; Brett, M.L.; Harrison, J.; Coole, S.F.; Mason, D.P.; Jennings, L.R.; Wong, M.; Tulasi, V.; Norman, D.; Lockey, P.M.; Williams, L.; Dossetter, A.G.; Griffen, E.J.; Thompson, M.J. An orally bioavailable, indole-3-glyoxylamide based series of tubulin polymerization inhibitors showing tumor gGrowth inhibition in a mouse Xenograft model of head and neck cancer. J. Med. Chem., 2015, 58, 9309-9333.
[17]
Marchand, P.; Antoine, M.; Le Baut, G.; Czech, M.; Baasner, S.; Günther, E. Synthesis and structure–activity relationships of N-aryl(indol-3-yl) glyoxamides as antitumor agents. Bioorg. Med. Chem., 2009, 17, 6715-6727.
[18]
Li, W.T.; Hwang, D.R.; Chen, C.P.; Shen, C.W.; Huang, C.L.; Chen, T.W.; Lin, C.H.; Chang, Y.L.; Chang, Y.Y.; Lo, Y.K.; Tseng, H.Y.; Lin, C.C.; Song, J.S.; Chen, H.C.; Chen, S.J.; Wu, S.H.; Chen, C.T. Synthesis and biological evaluation of N-Heterocyclic indolyl glyoxylamides as orally active anticancer agents. J. Med. Chem., 2003, 46, 1706-1715.
[19]
Fang, Z.; Liao, P.C.; Yang, Y.L.; Yang, F.L.; Chen, Y.L.; Lam, Y.; Hua, K.F.; Wu, S.H. Synthesis and biological evaluation of polyenylpyrrole derivatives as anticancer agents acting through caspases-dependent apoptosis. J. Med. Chem., 2010, 53, 7967-7978.
[20]
La Regina, G.; Bai, R.; Coluccia, A.; Famiglini, V.; Pelliccia, S.; Passacantilli, S.; Mazzoccoli, C.; Ruggieri, V.; Sisinni, L.; Bolognesi, A.; Rensen, W.M.; Miele, A.; Nalli, M.; Alfonsi, R.; Di Marcotullio, L.; Gulino, A.; Brancale, A.; Novellino, E.; Dondio, G.; Vultaggio, S.; Varasi, M.; Mercurio, C.; Hamel, E.; Lavia, P.; Silvestri, R. New pyrrole derivatives with potent tubulin polymerization inhibiting activity as anticancer agents including hedgehog-dependent cancer. J. Med. Chem., 2014, 57, 6531-6552.
[21]
Wang, S.; Wood, G.; Meades, C.; Griffiths, G.; Midgley, C.; McNae, I.; McInnes, C.; Anderson, S.; Jackson, W.; Mezna, M.; Yuill, R.; Walkinshaw, M.; Fischer, P.M. Synthesis and biological activity of 2-anilino-4-(1H-pyrrol-3-yl) pyrimidine CDK inhibitors. Bioorg. Med. Chem. Lett., 2004, 14, 4237-4240.
[22]
Menichincheri, M.; Albanese, C.; Alli, C.; Ballinari, D.; Bargiotti, A.; Caldarelli, M.; Ciavolella, A.; Cirla, A.; Colombo, M.; Colotta, F.; Croci, V.; D’Alessio, R.; D’Anello, M.; Ermoli, A.; Fiorentini, F.; Forte, B.; Galvani, A.; Giordano, P.; Isacchi, A.; Martina, K.; Molinari, A.; Moll, J.K.; Montagnoli, A.; Orsini, P.; Orzi, F.; Pesenti, E.; Pillan, A.; Roletto, F.; Scolaro, A.; Tatò, M.; Tibolla, M.; Valsasina, B.; Varasi, M.; Vianello, P.; Volpi, D.; Santocanale, C.; Vanotti, E. Cdc7 kinase inhibitors: 5-heteroaryl-3-carboxamido-2-aryl pyrroles as potential antitumor agents. 1. Lead finding. J. Med. Chem., 2010, 53, 7296-7315.
[23]
Ghasemi, M.; Ghadbeighi, S.; Amirhamzeh, A.; Tabatabai, S.A.; Ostad, S.N.; Shafiee, A.; Amini, M. Synthesis, molecular docking study, and cytotoxic activity of 1,3,5-triaryl pyrazole derivatives. Lett. Drug Des. Discov., 2016, 13, 121-128.
[24]
Ghadbegi, S.; Ostad, S.N.; Shafiee, A.; Amini, M. Synthesis and anticancer activity of 1,3,5-triaryl-1H-pyrazole. Lett. Drug Des. Discov., 2015, 12, 754-759.
[25]
Miralinaghi, P.; Salimi, M.; Amirhamzeh, A.; Norouzi, M.; Kandelousi, H.M.; Shafiee, A.; Amini, M. Synthesis, molecular docking study and anticancer activity of triaryl-1,2,4-oxadiazole. Med. Chem. Res., 2013, 22, 4253-4262.
[26]
Salehi, M.; Ostad, S.N.; Riazi, G.H.; Assadieskandar, A.; Shavi, T.C.; Shafiee, A.; Amini, M. Synthesis, cytotoxic evaluation, and molecular docking study of 4,5-diaryl-thiazole-2-thione analogs of combretastatin A-4 as microtubule-binding agents. Med. Chem. Res., 2014, 23, 1465-1473.
[27]
Zareian, B.; Ghadbeighi, S.; Amirhamzeh, A.; Ostad, S.N.; Shafiee, A.; Amini, M. Synthesis, molecular docking study and cytotoxic activity of 3,4-diaryl-5-(4-pyridinyl)-1,2,4-oxadiazole. Med. Chem., 2016, 12, 394-401.
[28]
Elahian, F.; Akbari, M.; Ghasemi, M.; Behtooee, N.; Taheri, M.; Amini, M. Synthesis and anticancer activity of 2,4,5-triaryl imidazole derivatives. Lett. Drug Des. Discov., 2014, 11, 840-843.
[29]
Peloquin, A.J.; Stone, R.L.; Avila, S.E.; Rudico, E.R.; Horn, C.B.; Gardner, K.A.; Ball, D.W.; Johnson, J.E.B.; Iacono, S.T.; Balaich, G.J. Synthesis of 1,3-diphenyl-6-alkyl/aryl-substituted fulvene chromophores: observation of π–π interactions in a 6-pyrene-substituted 1,3-diphenylfulvene. J. Org. Chem., 2012, 77, 6371-6376.
[30]
Stetter, H. A new method for the addition of aldehydes to activated double bonds, (iv.1) addition of aromatic and heterocyclic aldehydes to α, β-unsaturated ketones. Chem. Ber., 1974, 107, 2453-2458.
[31]
Assadieskandar, A.; Amini, M.; Ostad, S.N.; Riazi, G.H.; Shavi, T.C.; Shafiei, B.; Shafiee, A. Design, synthesis, cytotoxic evaluation and tubulin inhibitory activity of 4-aryl-5-(3,4,5-trimethoxy-phenyl)-2-alkylthio-1H-imidazole derivatives. Bioorg. Med. Chem., 2013, 21, 2703-2709.


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 15
ISSUE: 3
Year: 2019
Page: [231 - 239]
Pages: 9
DOI: 10.2174/1573406414666181015145945
Price: $58

Article Metrics

PDF: 34
HTML: 4
PRC: 2