Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry


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

Research Article

Synthesis and Anticancer Activity of Benzimidazole/Benzoxazole Substituted Triazolotriazines in Hepatocellular Carcinoma

Author(s): Sakineh Dadashpour, Tuba T. Küçükkılınç, Ayse Ercan, Seyed J. Hosseinimehr, Nima Naderi and Hamid Irannejad*

Volume 19, Issue 17, 2019

Page: [2120 - 2129] Pages: 10

DOI: 10.2174/1871520619666190808152051

Price: $65


Background: Receptor Tyrosine Kinases (RTK) are the main family of cell surface receptors for growth factors, hormones and cytokines which are responsible for cell growth and differentiation and are considered as an important therapeutic target in cancer.

Objective: The aim of this study was to design, synthesise and conduct the biological evaluation of benzimidazole/ benzoxazole substituted triazolotriazines as new anticancer agents.

Methods: A series of benzimidazolyl and benzoxazolyl-linked triazolotriazines 8a-e and 9a-e were synthesized as receptor tyrosine kinase inhibitors. Target compounds were evaluated in HGF-induced cell proliferation assay in A549, MCF-7, HepG2 and MDA-MB-231 cancer cells.

Results: Hepatocellular carcinoma was the most sensitive cell line towards the tested compounds and 8e was the most potent one on HepG2 cells with an IC50 value of 5.13µM which was close to crizotinib (HepG2 IC50 = 4.35µM) as a standard c-Met kinase inhibitor. c-Met kinase assay of 8e showed that this compound is not capable of inhibiting this enzyme and subsequently molecular docking confirmed the low affinity of 8e towards c- Met active site and its possible anticancer mechanism through VEGFR-2 inhibition.

Conclusion: Further in silico predictions revealed that 8e can be a drug candidate with favorable pharmacokinetic properties.

Keywords: Triazolotriazine, benzimidazole, benzoxazole, anticancer, VEGFR-2, c-Met.

Graphical Abstract
Li, C.; Ai, J.; Zhang, D.; Peng, X.; Chen, X.; Gao, Z.; Su, Y.; Zhu, W.; Ji, Y.; Chen, X.; Geng, M.; Liu, H. Design, synthesis, and biological evaluation of novel imidazo[1,2-a]pyridine derivatives as potent c-Met inhibitors. ACS Med. Chem. Lett., 2015, 6(5), 507-512.
[] [PMID: 26005523]
Gherardi, E.; Birchmeier, W.; Birchmeier, C.; Vande Woude, G. Targeting MET in cancer: Rationale and progress. Nat. Rev. Cancer, 2012, 12(2), 89-103.
[] [PMID: 22270953]
Peruzzi, B.; Bottaro, D.P. Targeting the c-Met signaling pathway in cancer. Clin. Cancer Res., 2006, 12(12), 3657-3660.
[] [PMID: 16778093]
Shibuya, M. Vascular Endothelial Growth Factor (VEGF) and its receptor (VEGFR) signaling in angiogenesis: A crucial target for anti- and pro-angiogenic therapies. Genes Cancer, 2011, 2(12), 1097-1105.
[] [PMID: 22866201]
Claridge, S.; Raeppel, F.; Granger, M.C.; Bernstein, N.; Saavedra, O.; Zhan, L.; Llewellyn, D.; Wahhab, A.; Deziel, R.; Rahil, J.; Beaulieu, N.; Nguyen, H.; Dupont, I.; Barsalou, A.; Beaulieu, C.; Chute, I.; Gravel, S.; Robert, M.F.; Lefebvre, S.; Dubay, M.; Pascal, R.; Gillespie, J.; Jin, Z.; Wang, J.; Besterman, J.M.; MacLeod, A.R.; Vaisburg, A. Discovery of a novel and potent series of thieno[3,2-b]pyridine-based inhibitors of c-Met and VEGFR2 tyrosine kinases. Bioorg. Med. Chem. Lett., 2008, 18(9), 2793-2798.
[] [PMID: 18434145]
Ibrahim, H.A.; Awadallah, F.M.; Refaat, H.M.; Amin, K.M. Molecular docking simulation, synthesis and 3D pharmacophore studies of novel 2-substituted-5-nitro-benzimidazole derivatives as anticancer agents targeting VEGFR-2 and c-Met. Bioorg. Chem., 2018, 77, 457-470.
[] [PMID: 29453077]
Shi, L.; Wu, T.T.; Wang, Z.; Xue, J.Y.; Xu, Y.G. Discovery of quinazolin-4-amines bearing benzimidazole fragments as dual inhibitors of c-Met and VEGFR-2. Bioorg. Med. Chem., 2014, 22(17), 4735-4744.
[] [PMID: 25082515]
Ibrahim, H.A.; Awadallah, F.M.; Refaat, H.M.; Amin, K.M. Design, synthesis and molecular modeling study for some new 2-substituted benzimidazoles as dual inhibitors for VEGFR-2 and c-Met. Future Med. Chem., 2018, 10(5), 493-509.
[] [PMID: 29431476]
Ibrahim, H.S.; Albakri, M.E.; Mahmoud, W.R.; Allam, H.A.; Reda, A.M.; Abdel-Aziz, H.A. Synthesis and biological evaluation of some novel thiobenzimidazole derivatives as anti-renal cancer agents through inhibition of c-MET kinase. Bioorg. Chem., 2019, 85, 337-348.
[] [PMID: 30658233]
Cho, S.Y.; Han, S.Y.; Ha, J.D.; Ryu, J.W.; Lee, C.O.; Jung, H.; Kang, N.S.; Kim, H.R.; Koh, J.S.; Lee, J. Discovery of aminopyridines substituted with benzoxazole as orally active c-Met kinase inhibitors. Bioorg. Med. Chem. Lett., 2010, 20(14), 4223-4227.
[] [PMID: 20570511]
Lee, J.; Han, S.Y.; Jung, H.; Yang, J.; Choi, J.W.; Chae, C.H.; Park, C.H.; Choi, S.U.; Lee, K.; Ha, J.D.; Lee, C.O.; Ryu, J.W.; Kim, H.R.; Koh, J.S.; Cho, S.Y. Synthesis and structure-activity relationship of aminopyridines with substituted benzoxazoles as c-Met kinase inhibitors. Bioorg. Med. Chem. Lett., 2012, 22(12), 4044-4048.
[] [PMID: 22579487]
Dadashpour, S.; Kϋçϋkkılınç, T.T.; Ayazgök, B.; Hosseinimehr, S.J.; Chippindale, A.M.; Foroumadi, A.; Irannejad, H. Discovery of novel 1,2,4-triazolo-1,2,4-triazines with thiomethylpyridine hinge binders as potent c-Met kinase inhibitors. Future Med. Chem., 2019, 11(10), 1119-1136.
[] [PMID: 31280674]
Akbari, A. Phenylglyoxal. Synlett, 2012, 23(6), 951-952.
Chen, F.; Wang, Y.; Ai, J.; Zhan, Z.; Lv, Y.; Liang, Z.; Luo, C.; Mei, D.; Geng, M.; Duan, W. O-linked triazolotriazines: Potent and selective c-Met inhibitors. ChemMedChem, 2012, 7(7), 1276-1285.
[] [PMID: 22539497]
Zhan, Z.; Peng, X.; Liu, Q.; Chen, F.; Ji, Y.; Yao, S.; Xi, Y.; Lin, Y.; Chen, T.; Xu, Y.; Ai, J.; Geng, M.; Duan, W. Discovery of 6-(difluoro(6-(4-fluorophenyl)-[1,2,4]triazolo[4,3-b][1,2,4]triazin-3-yl)methyl)quinoline as a highly potent and selective c-Met inhibitor. Eur. J. Med. Chem., 2016, 116, 239-251.
[] [PMID: 27061987]
Irannejad, H.; Kebriaieezadeh, A.; Zarghi, A.; Montazer-Sadegh, F.; Shafiee, A.; Assadieskandar, A.; Amini, M. Synthesis, docking simulation, biological evaluations and 3D-QSAR study of 5-Aryl-6-(4-methylsulfonyl)-3-(metylthio)-1,2,4-triazine as selective cyclooxygenase-2 inhibitors. Bioorg. Med. Chem., 2014, 22(2), 865-873.
[] [PMID: 24361187]
El-Sayed, W.A.; Nassar, I.F.; Abdel-Rahman, A.A.H. Synthesis and antitumor activity of new 1,2,4-triazine and [1,2,4]triazolo[4,3- b][1,2,4]triazine derivatives and Their thioglycoside and acyclic Cnucleoside analogs. J. Het. Chem, 2011, 48(1), 135-143.
[ WOS:000287169400018]
Dadashpour, S.; Tuylu Kucukkilinc, T.; Unsal Tan, O.; Ozadali, K.; Irannejad, H.; Emami, S. Design, synthesis and in vitro study of 5,6-diaryl-1,2,4-triazine-3-ylthioacetate derivatives as COX-2 and β-amyloid aggregation inhibitors. Arch. Pharm. (Weinheim), 2015, 348(3), 179-187.
[] [PMID: 25690564]
Suresh, N.; Durgarao, B.V.; Ratnakar, A.; Kumar Kolli, S.; Ashraf Ashfaq, M.; Basaveswara Rao, M.V. Pal, M. Ultrasound-assisted 3-component reaction in acetic acid alone: Catalyst/promoter/ligand free synthesis of bioactive pyrazolo[1,5-a]pyrimidines. Lett. Drug Des. Discov., 2017, 14(10), 1176-1183.
Huang, J.; Tang, Q.; Wang, C.; Yu, H.; Feng, Z.; Zhu, J. Molecularly targeted therapy of human hepatocellular carcinoma xenografts with radio-iodinated anti-VEGFR2 murine-human chimeric fab. Sci. Rep., 2015, 5, 10660.
[] [PMID: 26021484]
Peng, S.; Wang, Y.; Peng, H.; Chen, D.; Shen, S.; Peng, B.; Chen, M.; Lencioni, R.; Kuang, M. Autocrine vascular endothelial growth factor signaling promotes cell proliferation and modulates sorafenib treatment efficacy in hepatocellular carcinoma. Hepatology, 2014, 60(4), 1264-1277.
[] [PMID: 24849467]
Mahfouz, N.; Tahtouh, R.; Alaaeddine, N.; El Hajj, J.; Sarkis, R.; Hachem, R.; Raad, I.; Hilal, G. Gastrointestinal cancer cells treatment with bevacizumab activates a VEGF autoregulatory mechanism involving telomerase catalytic subunit hTERT via PI3K-AKT, HIF-1α and VEGF receptors. PLoS One, 2017, 12(6)e0179202
[] [PMID: 28594907]
Xie, C.; Wan, X.; Quan, H.; Zheng, M.; Fu, L.; Li, Y.; Lou, L. Preclinical characterization of anlotinib, a highly potent and selective vascular endothelial growth factor receptor-2 inhibitor. Cancer Sci., 2018, 109(4), 1207-1219.
[] [PMID: 29446853]
Tai, W.; Lu, T.; Yuan, H.; Wang, F.; Liu, H.; Lu, S.; Leng, Y.; Zhang, W.; Jiang, Y.; Chen, Y. Pharmacophore modeling and virtual screening studies to identify new c-Met inhibitors. J. Mol. Model., 2012, 18(7), 3087-3100.
[] [PMID: 22203475]
Cui, J.J.; McTigue, M.; Nambu, M.; Tran-Dubé, M.; Pairish, M.; Shen, H.; Jia, L.; Cheng, H.; Hoffman, J.; Le, P.; Jalaie, M.; Goetz, G.H.; Ryan, K.; Grodsky, N.; Deng, Y.L.; Parker, M.; Timofeevski, S.; Murray, B.W.; Yamazaki, S.; Aguirre, S.; Li, Q.; Zou, H.; Christensen, J. Discovery of a novel class of exquisitely selective mesenchymal-epithelial transition factor (c-MET) protein kinase inhibitors and identification of the clinical candidate 2-(4-(1-(quinolin-6-ylmethyl)-1H-[1,2,3]triazolo[4,5-b]pyrazin-6-yl)-1H-pyrazol-1-yl)ethanol (PF-04217903) for the treatment of cancer. J. Med. Chem., 2012, 55(18), 8091-8109.
[] [PMID: 22924734]
Hosseini Balef, S.S.; Piramoon, M.; Hosseinimehr, S.J.; Irannejad, H. In vitro and in silico evaluation of P-glycoprotein inhibition through 99m Tc-methoxyisobutylisonitrile uptake. Chem. Biol. Drug Des., 2019, 93(3), 283-289.
[] [PMID: 30270513]

Rights & Permissions Print Export Cite as
© 2024 Bentham Science Publishers | Privacy Policy