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Anti-Cancer Agents in Medicinal Chemistry

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

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Research Article

Heterocyclization of 2-Arylidenecyclohexan-1,3-dione: Synthesis of Thiophene, Thiazole, and Isoxazole Derivatives with Potential Antitumor Activities

Author(s): Nadia Y. Megally Abdo*, Rafat M. Mohareb and Waleed N. Al-darkazali

Volume 20, Issue 3, 2020

Page: [335 - 345] Pages: 11

DOI: 10.2174/1871520619666190730103425

Price: $65

Abstract

Background: Thiophene, thiazole, and isoxazole derivatives are present in a wide range of natural and synthetic compounds with heterogeneous pharmacological activity. Due to their structural diversity, they are some of the most versatile classes of compounds for anticancer drug design and discovery.

Objective: Thiophene, thiazole, and isoxazole derivatives were herein designed with a dual purpose: as antiproliferative agents and kinase inhibitors.

Methods: The test compounds were synthesized in moderate to high yields through a simple methodology. Tetrahydrobenzo[b]thiophen-5-one derivatives 5a-f were prepared from the reaction of 2-arylidencyclohexan- 1,3-dione 3a-c with elemental sulfur and either of malononitrile (4a) or ethyl cyanoacetate (4b) in 1,4-dioxan in the presence of triethylamine. Compounds 5a,b were used for the synthesis of thiophene, thiazole, and isoxazole derivatives through their reactions with different chemical reagents.

Results: Antiproliferative evaluations, c-Met kinase, and Pim-1 kinase inhibitions were performed where some compounds revealed high activities. In all cases, antiproliferative activity and the kinase inhibitions were performed against six cancer cell lines and five tyrosine kinases, respectively. Where the most cytotoxic compounds were 3c, 5d, and 16c with IC50’s 0.29, 0.68, and 0.42μM, respectively, against the A549 cell line.

Conclusion: The anti-proliferative activities of the newly synthesized compounds were evaluated against the six cancer cell lines (A549, HT-29, MKN-45, U87MG, SMMC-7721, and H460). The most potent compounds toward the cancer cell lines (3a, 3c, 5d, 7c, 11c, 16a, and 16c) were further investigated towards the five tyrosine kinases (c-kit, FIT-3, VEGFR-2, EGFR, and PDGFR). Compounds 3c, 5d, and 16c were selected for testing of their inhibition for the Pim-1 kinase due to their anti-proliferation activities against the cancer cell lines and their high activities against the tyrosine kinases.

Keywords: Cyclohexan-1, 3-dione, thiophene, thiazole, isoxazole, anti-proliferative activity, tyrosine kinases, Pim-1 kinase.

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[1]
Wang, L.; Wu, H.; Wang, L.; Zhang, H.; Lu, J.; Liang, Z.; Liu, T. Asporin promotes pancreatic cancer cell invasion and migration by regulating the epithelial-to-mesenchymal transition (EMT) through both autocrine and paracrine mechanisms. Cancer Lett., 2017, 398, 24-36.
[http://dx.doi.org/10.1016/j.canlet.2017.04.001] [PMID: 28400334]
[2]
Ou, S.I.; Lee, T.K.; Young, L.; Fernandez-Rocha, M.Y.; Pavlick, D.; Schrock, A.B.; Zhu, V.W.; Milliken, J.; Ali, S.M.; Gitlitz, B.J. Dual occurrence of ALK G1202R solvent front mutation and small cell lung cancer transformation as resistance mechanisms to second generation ALK inhibitors without prior exposure to crizotinib. Pitfall of solely relying on liquid re-biopsy? Lung Cancer, 2017, 106, 110-114.
[http://dx.doi.org/10.1016/j.lungcan.2017.02.005] [PMID: 28285684]
[3]
Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. Cancer incidence and mortality worlwide: sources, methods and major patterns in GLOBOCAN 2012. Int. J. Cancer, 2015, 136, 359-386.
[http://dx.doi.org/10.1002/ijc.29210]
[4]
Almeida, V.L.; Leitão, L.; Barret, L.C.; Montanari, C.A.; Donnici, C.L.; Lopes, M.T.P. Lopes Cãncer e agentes antineoplâsicos ciclocelular especáficos e ciclo-celular nío especáficos que interagem com o DNA. Uma introduçío. Quim. Nova, 2005, 28, 118-129.
[http://dx.doi.org/10.1590/S0100-40422005000100021]
[5]
Akhdar, H.; Legendre, C.; Aninat, C.; Morel, F. Anticancer drug metabolism:chemotherapy resistance and new therapeutic approaches.Topics on Drug Metabolism; Paxton, J., Ed.; InTech: Rijeka, 2012.
[http://dx.doi.org/10.5772/30015]
[6]
Luqmani, Y.A. Mechanisms of drug resistance in cancer chemotherapy. Med. Princ. Pract., 2005, 14(Suppl. 1), 35-48.
[http://dx.doi.org/10.1159/000086183] [PMID: 16103712]
[7]
Ismael, G.F.; Rosa, D.D.; Mano, M.S.; Awada, A. Novel cytotoxic drugs: old challenges, new solutions. Cancer Treat. Rev., 2008, 34(1), 81-91.
[http://dx.doi.org/10.1016/j.ctrv.2007.08.001] [PMID: 17905518]
[8]
Narang, A.S.; Desai, D.S. Anticancer drug development: unique aspects of pharmaceutical development.Pharmaceutical Perspectives of Cancer Therapeutics; Lu, Y; Mahato, R.I., Ed.; Springer Science, New York, 2009.
[http://dx.doi.org/10.1007/978-1-4419-0131-6_2]
[9]
Ferreira, D.; Adega, F.; Chaves, R. The importance of cancer cell lines as in vitro models in cancer methylome analysis and anticancer drugs testing.Oncogenomics, Cancer Proteomics -Novel pproaches in Biomarkers Discovery. Therapeutic Targets in Cancer; 1st ed; Camarillo, C.L.; Ocampo, E.A., Eds.; InTech: Rijeka, 2013.
[http://dx.doi.org/10.5772/53110]
[10]
Mishra, R.; Jha, K.K.; Kumar, S.; Tomer, I.S. Synthesis, properties and biological activity of thiophene: a review. Pharma Chem., 2011, 3, 38-54.
[11]
Meotti, F.C.; Silva, D.O.; Dos Santos, A.R.; Zeni, G.; Rocha, J.B.; Nogueira, C.W. Thiophenes and furans derivatives: a new class of potential pharmacological agents. Environ. Toxicol. Pharmacol., 2003, 15(1), 37-44.
[http://dx.doi.org/10.1016/j.etap.2003.08.008] [PMID: 21782678]
[12]
Chaudhary, A.; Jha, K.K.; Kumar, S. Biological diversity of thiophene: A Review. J. Adv. Sci. Res., 3, 3-10. 2012
[13]
Mohammad, A.I.C.; Satyendra, D.; Apurba, T.; Patel, M.; Monika, K.; Girish, K.; Mohan, S.; Saravanan, J. Synthesis and antimicrobial screening of some novel substituted thiophenes. Hyg. J. Drugs Med., 2012, 4, 112-118.
[14]
Wermuth, C.G. The Practice of Medicinal Chemistry. In: Academic Press; 3rd ed; London, 2011.
[15]
Puterová, Z.; Krutosíková, A.; Végh, D. Gewald reaction: synthesis, properties and applications of substituted 2-aminothiophenes. ARKIVOC, 2010, 1, 209-246.
[16]
Huang, X.; Liu, J.; Ren, J.; Wang, T.; Chen, W.; Zeng, B. A facile and practical one-pot synthesis of multisubstituted 2 -aminothiophenes via imidazole-catalyzed Gewald reaction. Tetrahedron, 2011, 67, 6202-6205.
[http://dx.doi.org/10.1016/j.tet.2011.06.061]
[17]
Liang, C.; Tang, Z.; Qian, W.; Shi, C.; Song, H. Ultrasound-promoted synthesis of 2-aminothiophenes accelerated by DABCO utilizing PEG-200 as solvent. J. Chem. Pharm. Res., 2014, 6, 798-802.
[18]
Meltzer, H.Y.; Fibiger, H.C. Olanzapine: a new typical antipsychotic drug. Neuropsychopharmacology, 1996, 14(2), 83-85.
[http://dx.doi.org/10.1016/0893-133X(95)00197-L] [PMID: 8822530]
[19]
Yasuda, H.; Izumi, N.; Shimada, O.; Kobayakawa, T.; Nakanishi, M. The protective effect of tinoridine against carbon tetrachloride hepatotoxicity. Toxicol. Appl. Pharmacol., 1980, 52(3), 407-413.
[http://dx.doi.org/10.1016/0041-008X(80)90335-X] [PMID: 6892737]
[20]
Arora, M.; Saravanan, J.; Mohan, S.; Bhattacharjee, S. Synthesis, characterization and antimicrobial activity of some schiff bases of 2-amino-n-(pacetamidophenylcarboxamido)-4,5,6,7-tetramethylene thiophenes. Int. J. Pharm. Pharm. Sci., 2013, 5, 315-319.
[21]
Rao, S.D.; Rasheed, S.; Basha, T.S.K.; Raju, N.C.; Naresh, K. SiO2/ZnCl2 catalyzed ɑ–aminophosphonates and phosphonated N-(substitued phenyl) sulfonamides of 2-aminothiophene synthesis and biological evaluation. Pharma Chem., 2013, 5, 61-74.
[22]
Khan, K.M.; Ullah, Z.; Lodhi, M.A.; Jalil, S.; Choudhary, M.I. Atta-Ur-Rahman, Synthesis and anti-inflammatory activity of some selected aminothiophene analogs. J. Enzyme Inhib. Med. Chem., 2006, 21(2), 139-143.
[http://dx.doi.org/10.1080/14756360500480418] [PMID: 16789427]
[23]
Fortes, A.C.; Almeida, A.A.; Mendonça-Júnior, F.J.; Freitas, R.M.; Soares-Sobrinho, J.L.; de La Roca Soares, M.F. Anxiolytic properties of new chemical entity, 5TIO1. Neurochem. Res., 2013, 38(4), 726-731.
[http://dx.doi.org/10.1007/s11064-013-0970-y] [PMID: 23334713]
[24]
Rodrigues, K.A.; Dias, C.N.; Néris, P.L. Rocha, Jda.C.; Scotti, M.T.; Scotti, L.; Mascarenhas, S.R.; Veras, R.C.; de Medeiros, I.A.; Keesen, Tde.S.; de Oliveira, T.B.; de Lima, Mdo.C.; Balliano, T.L.; de Aquino, T.M.; de Moura, R.O.; Mendonça Junior, F.J.; de Oliveira, M.R. 2-Amino-thiophene derivatives present antileishmanial activity mediated by apoptosis and immunomodulation in vitro. Eur. J. Med. Chem., 2015, 106, 1-14.
[http://dx.doi.org/10.1016/j.ejmech.2015.10.011] [PMID: 26513640]
[25]
Duffy, J.L.; Kirk, B.A.; Konteatis, Z.; Campbell, E.L.; Liang, R.; Brady, E.J.; Candelore, M.R.; Ding, V.D.H.; Jiang, G.; Liu, F.; Qureshi, S.A.; Saperstein, R.; Szalkowski, D.; Tong, S.; Tota, L.M.; Xie, D.; Yang, X.; Zafian, P.; Zheng, S.; Chapman, K.T.; Zhang, B.B.; Tata, J.R. Discovery and investigation of a novel class of thiophene-derived antagonists of the human glucagon receptor. Bioorg. Med. Chem. Lett., 2005, 15(5), 1401-1405.
[http://dx.doi.org/10.1016/j.bmcl.2005.01.003] [PMID: 15713396]
[26]
Abo-Salem, H.M.; El-Sawy, E.R.; Fathy, A.; Mandour, A.H. Synthesis, antifungal activity, and molecular docking study of some novel highly substituted 3-indolylthiophene derivatives. Egypt. Pharm. J., 2014, 13, 71-86.
[27]
Gouda, M.A.; Eldien, H.F.; Girges, M.M.; Berghot, M.A. Synthesis and antioxidante activity of novel series of naphthoquinone derivatives attached to benzothiophene moiety. Med. Chem., 2013, 2, 2228-2232.
[28]
Jagadish, E.R.; Mohan, S.; Saravanan, J.; Satyendra, D.; Swetha, S.P.; Apurba, T.; Manoj, K.; Rama, K.S. Synthesis and in-vitro anti-platelet aggregation activity of some new substituted thiophenes. Hyg. J. Drugs Med., 2013, 5, 87-96.
[29]
Liu, L.; Siegmund, A.; Xi, N.; Kaplan-Lefko, P.; Rex, K.; Chen, A.; Lin, J.; Moriguchi, J.; Berry, L.; Huang, L.; Teffera, Y.; Yang, Y.; Zhang, Y.; Bellon, S.F.; Lee, M.; Shimanovich, R.; Bak, A.; Dominguez, C.; Norman, M.H.; Harmange, J.C.; Dussault, I.; Kim, T.S. Discovery of a potent, selective, and orally bioavailable c-Met inhibitor: 1-(2-hydroxy-2-methylpropyl)-N-(5-(7-methoxyquinolin-4-yloxy)pyridin-2-yl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (AMG 458). J. Med. Chem., 2008, 51(13), 3688-3691.
[http://dx.doi.org/10.1021/jm800401t] [PMID: 18553959]
[30]
Peach, M.L.; Tan, N.; Choyke, S.J.; Giubellino, A.; Athauda, G.; Burke, T.R., Jr; Nicklaus, M.C.; Bottaro, D.P.; Bottaro, D.P. Directed discovery of agents targeting the Met tyrosine kinase domain by virtual screening. J. Med. Chem., 2009, 52(4), 943-951.
[http://dx.doi.org/10.1021/jm800791f] [PMID: 19199650]
[31]
De Bacco, F.; Luraghi, P.; Medico, E.; Reato, G.; Girolami, F.; Perera, T.; Gabriele, P.; Comoglio, P.M.; Boccaccio, C. Induction of MET by ionizing radiation and its role in radioresistance and invasive growth of cancer. J. Natl. Cancer Inst., 2011, 103(8), 645-661.
[http://dx.doi.org/10.1093/jnci/djr093] [PMID: 21464397]
[32]
Ariëns, E.J. Domestication of chemistry by design of safer chemicals: structure-activity relationships. Drug Metab. Rev., 1984, 15(3), 425-504.
[http://dx.doi.org/10.3109/03602538409029970] [PMID: 6386409]
[33]
Miller, J.A.; Miller, E.C. Origins of human cancer. In: Cold Spring Harbor Laboratory; Cold Spring Harbor, 1977; pp. 605-627.
[34]
Guernon, J.M.; Wu, Y.J. 3-Bromocyclohexane-1,2-dione as a useful reagent for Hantzsch synthesis of thiazoles and the synthesis of related heterocycles. Tetrahedron Lett., 2011, 52(28), 3633-3635.
[http://dx.doi.org/10.1016/j.tetlet.2011.05.028]
[35]
Kamila, S.; Mendoza, K.; Biehl, E.R. Microwave-assisted Hantzsch thiazole synthesis of N-phenyl-4-(6-phenylimidazo[2,1-b]thiazol-5-yl)thiazol-2-amines from the reaction of 2-chloro-1-(6-phenylimidazo[2,1-b]thiazol-5-yl)ethanones and thioureas. Tetrahedron Lett., 2012, 53(37), 4921-4924.
[http://dx.doi.org/10.1016/j.tetlet.2012.06.116] [PMID: 23175584]

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