Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Author(s): Umair Ilyas, Lina Tariq Alkury, Shagufta Naaz, Syed Aun Muhammad, Humaira Nadeem, Reem Altaf, Shahiq uz Zaman, Muhammad Faheem, Imran Sajid, Mohsin Tasawar Cheema, Abdul Mannan, Fawad Ali Shah* and Shupeng Li*

DOI: 10.2174/1871520622666211228105556

DownloadDownload PDF Flyer Cite As
Cytotoxic Evaluation and Molecular Docking Studies of Aminopyridine Derivatives as Potential Anticancer Agents

Page: [2599 - 2606] Pages: 8

  • * (Excluding Mailing and Handling)

Abstract

Background: The development of resistance to available anticancer drugs is increasingly becoming a major challenge and new chemical entities could be unveiled to compensate for this therapeutic failure.

Objectives: The current study demonstrated whether N-protected and deprotected amino acid derivatives of 2- aminopyridine could attenuate tumor development using colorectal cancer cell lines.

Methods: Biological assays were performed to investigate the anticancer potential of synthesized compounds. The in silico ADME profiling and docking studies were also performed by docking the designed compounds against the active binding site of beta-catenin (CTNNB1) to analyze the binding mode of these compounds. Four derivatives 4a, 4b, 4c, and 4d were selected for investigation of in vitro anticancer potential using colorectal cancer cell line HCT 116. The anti-tumor activities of synthesized compounds were further validated by evaluating the inhibitory effects of these compounds on the target protein beta-catenin through in vitro enzyme inhibitory assay.

Results: The docking analysis revealed favorable binding energies and interactions with the target proteins. The in vitro MTT assay on colorectal cancer cell line HCT 116 and HT29 revealed potential anti-tumor activities with an IC50 range of 3.7-8.1μM and 3.27-7.7 μM, respectively. The inhibitory properties of these compounds on the concentration of beta-catenin by ELISA revealed significant percent inhibition of target protein at 100 μg/ml.

Conclusion: In conclusion, the synthesized compounds showed significant anti-tumor activities both in silico and in vitro, having potential for further investigating its role in colorectal cancer.

Keywords: Colorectal cancer, 2-aminopyridine, heterocyclic, in silico, beta-catenin, anti-tumor.

Graphical Abstract

[1]
Provenzale, D.; Ness, R.M.; Llor, X.; Weiss, J.M.; Abbadessa, B.; Cooper, G.; Early, D.S.; Friedman, M.; Giardiello, F.M.; Glaser, K.; Gurudu, S.; Halverson, A.L.; Issaka, R.; Jain, R.; Kanth, P.; Kidambi, T.; Lazenby, A.J.; Maguire, L.; Markowitz, A.J.; May, F.P.; Mayer, R.J.; Mehta, S.; Patel, S.; Peter, S.; Stanich, P.P.; Terdiman, J.; Keller, J.; Dwyer, M.A.; Ogba, N. NCCN Guidelines Insights: Colorectal can-cer screening, Version 2.2020. J. Natl. Compr. Canc. Netw., 2020, 18(10), 1312-1320.
[http://dx.doi.org/10.6004/jnccn.2020.0048] [PMID: 33022639]
[2]
Rawla, P.; Sunkara, T.; Barsouk, A. Epidemiology of colorectal cancer: Incidence, mortality, survival, and risk factors. Prz. Gastroenterol., 2019, 14(2), 89-103.
[http://dx.doi.org/10.5114/pg.2018.81072] [PMID: 31616522]
[3]
Favoriti, P.; Carbone, G.; Greco, M.; Pirozzi, F.; Pirozzi, R.E.; Corcione, F. Worldwide burden of colorectal cancer: a review. Updates Surg., 2016, 68(1), 7-11.
[http://dx.doi.org/10.1007/s13304-016-0359-y] [PMID: 27067591]
[4]
Low, EE; Demb, J; Liu, L; Earles, A; Bustamante, R; Williams, C.D.; Provenzale, D.; Kaltenbach, T.; Gawron, A.J.; Martinez, M.E.; Gupta, S. Risk factors for early-onset colorectal cancer. Gastroenterology, 2020, 159(2), 492-501. e7.,
[http://dx.doi.org/10.1053/j.gastro.2020.01.004] [PMID: 31926997]
[5]
Palaghia, M. Metastatic colorectal cancer: Review of diagnosis and treatment options. Jurnalul de Chirurgie., 2015, 10(4).
[http://dx.doi.org/10.7438/1584-9341-10-4-2]
[6]
Assi, R.; Mukherji, D.; Haydar, A.; Saroufim, M.; Temraz, S.; Shamseddine, A. Metastatic colorectal cancer presenting with bone marrow metastasis: A case series and review of literature. J. Gastrointest. Oncol., 2016, 7(2), 284-297.
[http://dx.doi.org/10.3978/j.issn.2078-6891.2015.092] [PMID: 27034798]
[7]
Nagafuchi, A.; Takeichi, M. Transmembrane control of cadherin-mediated cell adhesion: A 94 kDa protein functionally associated with a specific region of the cytoplasmic domain of E-cadherin. Cell Regul., 1989, 1(1), 37-44.
[http://dx.doi.org/10.1091/mbc.1.1.37] [PMID: 2519616]
[8]
Ozawa, M.; Baribault, H.; Kemler, R. The cytoplasmic domain of the cell adhesion molecule uvomorulin associates with three independent proteins structurally related in different species. EMBO J., 1989, 8(6), 1711-1717.
[http://dx.doi.org/10.1002/j.1460-2075.1989.tb03563.x] [PMID: 2788574]
[9]
Tian, X.; Liu, Z.; Niu, B.; Zhang, J.; Tan, T.K.; Lee, S.R.; Zhao, Y.; Harris, D.C.; Zheng, G. E-cadherin/β-catenin complex and the epithelial barrier. J. Biomed. Biotechnol., 2011, 2011, 567305.
[http://dx.doi.org/10.1155/2011/567305] [PMID: 22007144]
[10]
Novellasdemunt, L.; Antas, P.; Li, V.S. Targeting Wnt signaling in colorectal cancer. A review in the theme: cell signaling: proteins, path-ways and mechanisms. Am. J. Physiol. Cell Physiol., 2015, 309(8), C511-C521.
[http://dx.doi.org/10.1152/ajpcell.00117.2015] [PMID: 26289750]
[11]
Williams, E.J.; Taylor, S.; Fairclough, P.; Hamlyn, A.; Logan, R.F.; Martin, D.; Riley, S.A.; Veitch, P.; Wilkinson, M.; Williamson, P.R.; Lombard, M. Are we meeting the standards set for endoscopy? Results of a large-scale prospective survey of endoscopic retrograde chol-angio-pancreatograph practice. Gut, 2007, 56(6), 821-829.
[http://dx.doi.org/10.1136/gut.2006.097543] [PMID: 17145737]
[12]
Zhan, T.; Rindtorff, N.; Boutros, M. Wnt signaling in cancer. Oncogene, 2017, 36(11), 1461-1473.
[http://dx.doi.org/10.1038/onc.2016.304] [PMID: 27617575]
[13]
Shahryar, M.; Shahramian, I.; Dehghani, S.M.; Noori, N.; Ataollahi, M. Lithophagia as a clue for celiac disease: a case report and literature review. Gastroenterol. Hepatol. Bed Bench, 2017, 10(1), 70-72.
[PMID: 28331568]
[14]
Hankey, W.; Frankel, W.L.; Groden, J. Functions of the APC tumor suppressor protein dependent and independent of canonical WNT signaling: Implications for therapeutic targeting. Cancer Metastasis Rev., 2018, 37(1), 159-172.
[http://dx.doi.org/10.1007/s10555-017-9725-6] [PMID: 29318445]
[15]
Shabaninejad, Z.; Vafadar, A.; Movahedpour, A.; Ghasemi, Y.; Namdar, A.; Fathizadeh, H.; Pourhanifeh, M.H.; Savardashtaki, A.; Mir-zaei, H. Circular RNAs in cancer: New insights into functions and implications in ovarian cancer. J. Ovarian Res., 2019, 12(1), 84.
[http://dx.doi.org/10.1186/s13048-019-0558-5] [PMID: 31481095]
[16]
Inamura, K. Colorectal cancers: An update on their molecular pathology. Cancers (Basel), 2018, 10(1), E26.
[http://dx.doi.org/10.3390/cancers10010026] [PMID: 29361689]
[17]
Hamada, Y.; Tagad, H.D.; Nishimura, Y.; Ishiura, S.; Kiso, Y. Tripeptidic BACE1 inhibitors devised by in-silico conformational structure-based design. Bioorg. Med. Chem. Lett., 2012, 22(2), 1130-1135.
[http://dx.doi.org/10.1016/j.bmcl.2011.11.102] [PMID: 22178553]
[18]
Hayakawa, M.; Kaizawa, H.; Kawaguchi, K.; Ishikawa, N.; Koizumi, T.; Ohishi, T.; Yamano, M.; Okada, M.; Ohta, M.; Tsukamoto, S.; Raynaud, F.I.; Waterfield, M.D.; Parker, P.; Workman, P. Synthesis and biological evaluation of imidazo[1,2-a]pyridine derivatives as novel PI3 kinase p110 inhibitors. Bioorg. Med. Chem., 2007, 15(1), 403-412.
[http://dx.doi.org/10.1016/j.bmc.2006.09.047] [PMID: 17049248]
[19]
Eri S.; Ke, S.; Barata, T.; Solmajer, T.; Anti Stankovi J.; Jurani Z.; Savi V.; Zloh, M. Target fishing and docking studies of the nov-el derivatives of aryl-aminopyridines with potential anticancer activity. Bioorg. Med. Chem., 2012, 20(17), 5220-5228.
[http://dx.doi.org/10.1016/j.bmc.2012.06.051] [PMID: 22841617]
[20]
Usifoh, C.O.; Lambert, D.M.; Wouters, J.; Scriba, G.K. Synthesis and anticonvulsant activity of N,N-phthaloyl derivatives of central nerv-ous system inhibitory amino acids. Arch. Pharm. (Weinheim), 2001, 334(10), 323-331.
[http://dx.doi.org/10.1002/1521-4184(200110)334:10<323:AID-ARDP323>3.0.CO;2-O] [PMID: 11759171]
[21]
Koroleva, E.; Ignatovich, Z.I.; Sinyutich, Y.V.; Gusak, K. Aminopyrimidine derivatives as protein kinases inhibitors. Molecular design, synthesis, and biologic activity. Russ. J. Org. Chem., 2016, 52(2), 139-177.
[http://dx.doi.org/10.1134/S1070428016020019]
[22]
Naz, S.; Shah, F.A.; Nadeem, H.; Sarwar, S.; Tan, Z.; Imran, M.; Ali, T.; Li, J.B.; Li, S. Amino acid conjugates of aminothiazole and ami-nopyridine as potential anticancer agents: Synthesis, molecular docking and in vitro evaluation. Drug Des. Devel. Ther., 2021, 15, 1459-1476.
[http://dx.doi.org/10.2147/DDDT.S297013] [PMID: 33833504]
[23]
Ilyas, U. uz Zaman S, Altaf R, Nadeem H, Muhammad SA. Genome wide meta-analysis of cDNA datasets reveals new target gene signa-tures of colorectal cancer based on systems biology approach. J. Biol. Res. (Thessalon.), 2020, 27, 8.
[http://dx.doi.org/10.1186/s40709-020-00118-1] [PMID: 32523911]
[24]
Finch, R.A.; Liu, M.; Grill, S.P.; Rose, W.C.; Loomis, R.; Vasquez, K.M.; Cheng, Y.; Sartorelli, A.C. Triapine (3-aminopyridine-2-carboxaldehyde- thiosemicarbazone): A potent inhibitor of ribonucleotide reductase activity with broad spectrum antitumor activity. Biochem. Pharmacol., 2000, 59(8), 983-991.
[http://dx.doi.org/10.1016/S0006-2952(99)00419-0] [PMID: 10692563]
[25]
Hill, M.D. Recent strategies for the synthesis of pyridine derivatives. Chemistry, 2010, 16(40), 12052-12062.
[http://dx.doi.org/10.1002/chem.201001100] [PMID: 20827696]
[26]
Barabási, A-L.; Gulbahce, N.; Loscalzo, J. Network medicine: A network-based approach to human disease. Nat. Rev. Genet., 2011, 12(1), 56-68.
[http://dx.doi.org/10.1038/nrg2918] [PMID: 21164525]
[27]
Li, S.; Huang, M.; Liu, Q.; Wang, D.; Wu, R.; Zhang, X.; Zhang, X.; Chen, W.; Duan, L. Serum expression of β-catenin is a potential detection marker in patients with colorectal cancer. Dis. Markers, 2019, 2019, 5070524.
[http://dx.doi.org/10.1155/2019/5070524] [PMID: 31781302]
[28]
Shang, S.; Hua, F.; Hu, Z-W. The regulation of β-catenin activity and function in cancer: Therapeutic opportunities. Oncotarget, 2017, 8(20), 33972-33989.
[http://dx.doi.org/10.18632/oncotarget.15687] [PMID: 28430641]
[29]
Kolligs, F.T.; Bommer, G.; Göke, B. Wnt/beta-catenin/tcf signaling: A critical pathway in gastrointestinal tumorigenesis. Digestion, 2002, 66(3), 131-144.
[http://dx.doi.org/10.1159/000066755] [PMID: 12481159]
[30]
MacDonald, B.T.; Tamai, K.; He, X. Wnt/beta β-catenin signaling: Components, mechanisms, and diseases. Dev. Cell, 2009, 17(1), 9-26.
[http://dx.doi.org/10.1016/j.devcel.2009.06.016] [PMID: 19619488]
[31]
Lee, S.H.; Richardson, R.L.; Dashwood, R.H.; Baek, S.J. Capsaicin represses transcriptional activity of β-catenin in human colorectal can-cer cells. J. Nutr. Biochem., 2012, 23(6), 646-655.
[http://dx.doi.org/10.1016/j.jnutbio.2011.03.009] [PMID: 21764279]
[32]
Yoshida, G.J. Applications of patient-derived tumor xenograft models and tumor organoids. J. Hematol. Oncol., 2020, 13(1), 4.
[http://dx.doi.org/10.1186/s13045-019-0829-z] [PMID: 31910904]
[33]
Wang, J.; Li, B.; Zhao, K.; Su, X. 2-amino-4-(1-piperidine) pyridine exhibits inhibitory effect on colon cancer through suppression of FOXA2 expression. 3 Biotechnology, 2019, 9(11), 384.
[http://dx.doi.org/10.1007/s13205-019-1915-1 ] [PMID: 31656722]
[34]
Huang, H.; Guzman-Perez, A.; Acquaviva, L.; Berry, V.; Bregman, H.; Dovey, J.; Gunaydin, H.; Huang, X.; Huang, L.; Saffran, D.; Serafi-no, R.; Schneider, S.; Wilson, C.; DiMauro, E.F. Structure-based design of 2-aminopyridine oxazolidinones as potent and selective tanky-rase inhibitors. ACS Med. Chem. Lett., 2013, 4(12), 1218-1223.
[http://dx.doi.org/10.1021/ml4003315] [PMID: 24900633]
[35]
Mohamed, S.F.; Kotb, E.R.; Abd El-Meguid, E.A.; Awad, H.M. Synthesis and anticancer activity of novel 2-substituted pyranopyridine derivatives. Res. Chem. Intermed., 2017, 43(1), 437-456.
[http://dx.doi.org/10.1007/s11164-016-2633-5]
[36]
Zhang, Z-H.; Wu, H-M.; Deng, S-N.; Cai, X-Y.; Yao, Y.; Mwenda, M.C. Design, synthesis, and anticancer activities of novel 2-amino-4-phenylthiazole Scaffold containing amide moieties. J. Chem., 2018, 2018, 4301910.
[http://dx.doi.org/10.1155/2018/4301910]