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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Uses of Cyclohexan-1,3-dione for the Synthesis of Thiazole, Pyrazole, Thiophene, Isoxazole and Pyran Derivatives with Antitumor Activities

Author(s): Rafat Milad Mohareb, Nadia Youssef Megally Abdo* and Waleed Nabeel Al-darkazali

Volume 17, Issue 5, 2020

Page: [597 - 609] Pages: 13

DOI: 10.2174/1570180816666190618115128

Price: $65

Abstract

Background: A wide range of thiazole, pyrazole and pyran derivatives gained special attention due to pharmacological activities especially therapeutic activities. Many pharmacological drugs containing the thiazole and pyrazole nuclei are known in the market.

Methods: The 2-arylidencyclohexan-1,3-dione 3a-c were the key starting compounds for many heterocyclic reactions to produce substituted heterocyclic derivatives.

Results: Antiproliferative activities of the produced compounds against six cancer cell lines A549, HT-29, MKN-45, U87MG, SMMC-7721 and H460 were measured in which the compounds showed high inhibition. The most promising compounds were tested against tyrosine kinases (c-Kit, Flt-3, VEGFR-2, EGFR, and PDGFR). Structure-Activity Relationship (SAR) was rationalized by assessing the varying structural features of the molecules. In addition, the most active compounds were selected for Pim-1 inhibition.

Conclusion: Thirty compounds were synthesized. Ten of them (3a, 3c, 5a, 5c, 7a, 10f, 11a, 13c, 16a and 16c) were the most active compounds for selected cancer cell lines. Compounds 3c, 5c, 7a, 10f, 13c and 16c showed high inhibition toward the tyrosine kinases while compounds 3c, 5c and 10f were the most potent to inhibit Pim-1.

Keywords: Cyclohexan-1, 3-dione, pyrazole, thiophene, pyran, anti-proliferative activity, tyrosine kinases.

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[1]
Fan, N.J.; Han, Y.Y.; Li, Y.F.; Gao, J.M.; Tang, J.J. Synthesis of novel 4′-acylamino modified 21E-benzylidene steroidal derivatives and their cytotoxic activities. Steroids, 2017, 123, 20-26.
[http://dx.doi.org/10.1016/j.steroids.2017.04.006] [PMID: 28483508]
[2]
Scherbakov, A.M.; Zavarzin, I.V.; Vorontsova, S.K.; Hajra, A.; Andreeva, O.E.; Yadykov, A.V.; Levina, I.S.; Volkova, Y.A.; Shirinian, V.Z. Synthesis and evaluation of the antiproliferative activity of benzylidenes of 16-dehydroprogesterone series. Steroids, 2018, 138, 91-101.
[http://dx.doi.org/10.1016/j.steroids.2018.06.013] [PMID: 29997047]
[3]
Gupta, N.; Rath, S.K.; Singh, J.; Qayum, A.; Singh, S.; Sangwan, P.L. Synthesis of novel benzylidene analogues of betulinic acid as potent cytotoxic agents. Eur. J. Med. Chem., 2017, 135, 517-530.
[http://dx.doi.org/10.1016/j.ejmech.2017.04.062] [PMID: 28500966]
[4]
Yan, Q.; Cao, R.; Yi, W.; Chen, Z.; Wen, H.; Ma, L.; Song, H. Inhibitory effects of 5-benzylidene barbiturate derivatives on mushroom tyrosinase and their antibacterial activities. Eur. J. Med. Chem., 2009, 44(10), 4235-4243.
[http://dx.doi.org/10.1016/j.ejmech.2009.05.023] [PMID: 19552984]
[5]
Bhanushali, U.; Rajendran, S.; Sarma, K.; Kulkarni, P.; Chatti, K.; Chatterjee, S.; Ramaa, C.S. 5-Benzylidene-2,4-thiazolidenedione derivatives: Design, synthesis and evaluation as inhibitors of angiogenesis targeting VEGR-2. Bioorg. Chem., 2016, 67, 139-147.
[http://dx.doi.org/10.1016/j.bioorg.2016.06.006] [PMID: 27388635]
[6]
Chen, Z.; Cai, D.; Mou, D.; Yan, Q.; Sun, Y.; Pan, W.; Wan, Y.; Song, H.; Yi, W. Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase inhibitors. Bioorg. Med. Chem., 2014, 22(13), 3279-3284.
[http://dx.doi.org/10.1016/j.bmc.2014.04.060] [PMID: 24857777]
[7]
Zuliani, V.; Carmi, C.; Rivara, M.; Fantini, M.; Lodola, A.; Vacondio, F.; Bordi, F.; Plazzi, P.V.; Cavazzoni, A.; Galetti, M.; Alfieri, R.R.; Petronini, P.G.; Mor, M. 5-Benzylidene-hydantoins: Synthesis and antiproliferative activity on A549 lung cancer cell line. Eur. J. Med. Chem., 2009, 44(9), 3471-3479.
[http://dx.doi.org/10.1016/j.ejmech.2009.01.035] [PMID: 19268405]
[8]
Sonmez, F.; Sevmezler, S.; Atahan, A.; Ceylan, M.; Demir, D.; Gencer, N.; Arslan, O.; Kucukislamoglu, M. Evaluation of new chalcone derivatives as polyphenol oxidase inhibitors. Bioorg. Med. Chem. Lett., 2011, 21(24), 7479-7482.
[http://dx.doi.org/10.1016/j.bmcl.2011.09.130] [PMID: 22055203]
[9]
Bhat, B.A.; Dhar, K.L.; Puri, S.C.; Saxena, A.K.; Shanmugavel, M.; Qazi, G.N. Synthesis and biological evaluation of chalcones and their derived pyrazoles as potential cytotoxic agents. Bioorg. Med. Chem. Lett., 2005, 15(12), 3177-3180.
[http://dx.doi.org/10.1016/j.bmcl.2005.03.121] [PMID: 15893928]
[10]
Choudary, B.M.; Lakshmi Kantam, M.; Kavita, B.; Venkat Reddy, Ch.; Figueras, F. Catalytic C-C bond formation promoted by Mg-Al-O-t-Bu hydrolacite. Tetrahedron, 2000, 56, 9357-9364.
[http://dx.doi.org/10.1016/S0040-4020(00)00906-6]
[11]
Prajapati, D.; Lekhok, K.C.; Sandhu, J.S.; Ghosh, A.C. Magnesium Perchlorate as efficient lewis acid for the knoevenagel condensation between β-diketones and aldehydes. J. Chem. Soc. Perkin, 1996, 1, 959-960.
[http://dx.doi.org/10.1039/P19960000959]
[12]
Khan, R.H.; Mathur, R.K.; Ghosh, A.C. Tellurium (IV). Tetrachloride Catalyzed Facile Knoevenagel Reaction. Synthetic Commun., 1996, 26, 683-686.
[13]
Tanaka, K. Solvent-Free Organic Synthesis; Wiley-VCH: Weinheim, 2003, pp. 93-136.
[http://dx.doi.org/10.1002/3527601821]
[14]
Tanaka, K.; Toda, F. Solvent-free organic synthesis. Chem. Rev., 2000, 100(3), 1025-1074.
[http://dx.doi.org/10.1021/cr940089p] [PMID: 11749257]
[15]
Obrador, E.; Castro, M.; Tamariz, J.; Zepeda, G.; Miranda, R.; Delgado, F. Knoevenagel condensation in heterogeneous phase catalyzed by IR Radiation and Tonsil Actisil FF. Synth. Commun., 1998, 28, 4649-4663.
[http://dx.doi.org/10.1080/00397919808004530]
[16]
Balalaie, S.; Nemati, N. One-pot preparation of coumarins by knoevenagel condensation in solvent-free condition under microwave irradiation. Heterocycl. Commun., 2001, 7, 67-72.
[http://dx.doi.org/10.1515/HC.2001.7.1.67]
[17]
Loupy, A.; Song, S.; Sohn, S.; Lee, Y.; Known, T. Solvent-free bentonite-catalyzed condensation of malonic acid and aromatic aldehydes under microwave irradiation. J. Chem. Soc. Perkin, 2001, 1, 1220-1222.
[http://dx.doi.org/10.1039/b009803p]
[18]
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]
[19]
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]
[20]
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]
[21]
Zhao, H.; Cui, G.; Jin, J.; Chen, X.; Xu, B. Synthesis and Pin1 inhibitory activity of thiazole derivatives. Bioorg. Med. Chem., 2016, 24(22), 5911-5920.
[http://dx.doi.org/10.1016/j.bmc.2016.09.049] [PMID: : 27692510]
[22]
Taha, M.; Ismail, N.H.; Imran, S.; Selvaraj, M.; Rahim, F. Synthesis of novel inhibitors of β-glucuronidase based on the benzothiazole skeleton and their molecular docking studies. RSC Advances, 2016, 6, 3003-3012.
[http://dx.doi.org/10.1039/C5RA23072A]
[23]
Mouri, K.; Saito, S.; Yamaguchi, S. Highly flexible π-expanded cyclooctatetraenes: Cyclic thiazole tetramers with head-to-tail connection. Angew. Chem. Int. Ed. Engl., 2012, 51(24), 5971-5975.
[http://dx.doi.org/10.1002/anie.201201265] [PMID: 22555989]
[24]
Shah, N.K.; Shah, N.M.; Patel, M.P.; Patel, R.G. Synthesis, characterization and antimicrobial activity of some new biquinoline derivatives containing a thiazole moiety. Chin. Chem. Lett., 2012, 23, 454-457.
[http://dx.doi.org/10.1016/j.cclet.2012.01.042]
[25]
Mukhopadhyay, C.; Ray, S. Rapid and straightforward one-pot expeditious synthesis of 2-amino-5-alkylidene-thiazol-4-ones at room temperature. Tetrahedron Lett., 2011, 52, 6431-6438.
[http://dx.doi.org/10.1016/j.tetlet.2011.09.090]
[26]
Heravi, M.M.; Moghimi, S. An efficient synthesis of thiazol-2-imine derivatives via a one-pot, three-component reaction. Tetrahedron Lett., 2012, 53, 392-394.
[http://dx.doi.org/10.1016/j.tetlet.2011.11.017]
[27]
Li, Z.; Yang, Q.; Qian, X. Novel heterocyclic family of phenyl naphthothiazole carboxamides derived from naphthalimides: synthesis, antitumor evaluation, and DNA photocleavage. Bioorg. Med. Chem., 2005, 13(9), 3149-3155.
[http://dx.doi.org/10.1016/j.bmc.2005.02.045] [PMID: 15809150]
[28]
Ahadi, S.; Shakibaei, G.I.; Mirzaei, P.; Bazgir, A. A clean synthesis of 3, 3-bis (5-amino-1h-pyrazol-4-yl)-indolin-2-one derivatives. Heterocycles, 2008, 75, 2293-2299.
[http://dx.doi.org/10.3987/COM-08-11391]
[29]
Fan, W.; Ye, Q.; Xu, H.W.; Jiang, B.; Wang, S.L.; Tu, S.J. Novel double [3 + 2 + 1] heteroannulation for forming unprecedented dipyrazolo-fused 2,6-naphthyridines. Org. Lett., 2013, 15(9), 2258-2261.
[http://dx.doi.org/10.1021/ol4008266] [PMID: 23597067]
[30]
Wang, J.J.; Feng, X.; Xun, Z.; Shi, D.Q.; Huang, Z.B. Multicomponent strategy to pyrazolo [3, 4-e]indolizine derivatives under microwave irradiation. J. Org. Chem., 2015, 80(16), 8435-8442.
[http://dx.doi.org/10.1021/acs.joc.5b01314] [PMID: 26193420]
[31]
Ahadi, S.; Ghahremanzadeh, R.; Mirzaei, P.; Bazgir, A. Synthesis of spiro [benzopyrazolo-naphthyridineindoline]-diones and spiro [chromenopyrazolopyridine-indoline]-diones by one-pot, three-component methods in water. Tetrahedron, 2009, 65, 9316-9321.
[http://dx.doi.org/10.1016/j.tet.2009.09.009]
[32]
Ryabukhin, S.V.; Granat, D.S.; Plaskon, A.S.; Shivanyuk, A.; Lukin, O. Synthesis of pyrazolo [3, 4-d]-4, 5-dihydropyrimidin-6-ones. Tetrahedron Lett., 2014, 55, 1846-1847.
[http://dx.doi.org/10.1016/j.tetlet.2014.01.131]
[33]
Schmitt, D.C.; Niljianskul, N.; Sach, N.W.; Trujillo, J.I. A Parallel Approach to 7-(Hetero)arylpyrazolo[1,5- a]pyrimidin-5-ones. ACS Comb. Sci., 2018, 20(5), 256-260.
[http://dx.doi.org/10.1021/acscombsci.8b00032] [PMID: 29618198]
[34]
Aggarwal, R.; Rani, C.; Kumar, R.; Garg, G.; Sharma, J. Synthesis of new bi (pyrazolo [1,5-a] pyrimidinyl)-7-one derivatives from dehydroacetic acid and its analogues as antibacterial agents. ARKIVOC, 2014, ii, 120-134.
[35]
Lichitsky, B.; Komogortsev, A.; Dudinov, A.; Krayushkin, M. Three-component condensation of 5-aminopyrazole derivatives with isatins and meldrum’s acid. Synthesis of 1, 7-dihydrospiro [pyrazolo [3, 4-b]-pyridine-4, 3′-indole]-2′, 6 (1′ h, 5h)-diones. Russ. Chem. Bull., 2009, 58, 1504-1508.
[http://dx.doi.org/10.1007/s11172-009-0202-4]
[36]
Chebanov, V.A.; Saraev, V.E.; Desenko, S.M.; Chernenko, V.N.; Shishkina, S.V.; Shishkin, O.V.; Kobzar, K.M.; Kappe, C.O. One-pot, multicomponent route to pyrazoloquinolizinones. Org. Lett., 2007, 9(9), 1691-1694.
[http://dx.doi.org/10.1021/ol070411l] [PMID: 17385876]
[37]
Jiang, B.; Fan, W.; Sun, M.Y.; Ye, Q.; Wang, S.L.; Tu, S.J.; Li, G. Domino reaction of arylglyoxals with pyrazol-5-amines: Selective access to pyrazolo-fused 1,7-naphthyridines, 1,3-diazocanes, and pyrroles. J. Org. Chem., 2014, 79(11), 5258-5268.
[http://dx.doi.org/10.1021/jo500823z] [PMID: 24833111]
[38]
Lin, Y.; Lang, S.A. New synthesis of isoxazoles and isothiazoles. A convenient synthesis of thioenaminones from enaminones. J. Org. Chem., 1980, 45, 4857-4860.
[http://dx.doi.org/10.1021/jo01312a011]
[39]
Nakamura, T.; Sato, M.; Kakinuma, H.; Miyata, N.; Taniguchi, K.; Bando, K.; Koda, A.; Kameo, K. Pyrazole and isoxazole derivatives as new, potent, and selective 20-hydroxy-5,8,11,14-eicosatetraenoic acid synthase inhibitors. J. Med. Chem., 2003, 46(25), 5416-5427.
[http://dx.doi.org/10.1021/jm020557k] [PMID: 14640550]
[40]
Wang, T.; Liu, J.; Zhong, H.; Chen, H.; Lv, Z.; Zhang, Y.; Zhang, M.; Geng, D.; Niu, C.; Li, Y.; Li, K. Synthesis and anti-tumor activity of novel ethyl 3-aryl-4-oxo-3,3a,4,6-tetrahydro-1H-furo[3,4-c]pyran-3a-carboxylates. Bioorg. Med. Chem. Lett., 2011, 21(11), 3381-3383.
[http://dx.doi.org/10.1016/j.bmcl.2011.04.003] [PMID: 21515044]
[41]
Babu, N.S.; Pasha, N.; Rao, K.T.; Prasad, P.S.; Lingaiah, N. A heterogeneous strong basic Mg/La mixed oxide catalyst for efficient synthesis of polyfunctionalized pyrans. Tetrahedron Lett., 2008, 49, 2730-2733.
[http://dx.doi.org/10.1016/j.tetlet.2008.02.154]
[42]
Romdhane, A. HichemBen Jannet, H.B. Synthesis of new pyran and pyranoquinoline derivatives. Arab. J. Chem., 2017, 10, S3128-S3134.
[http://dx.doi.org/10.1016/j.arabjc.2013.12.002]
[43]
Blume-Jensen, P.; Hunter, T. Oncogenic kinase signalling. Nature, 2001, 411(6835), 355-365.
[http://dx.doi.org/10.1038/35077225] [PMID: 11357143]
[44]
DiSalvo, J.; Bayne, M.L.; Conn, G.; Kwok, P.W.; Trivedi, P.G.; Soderman, D.D.; Palisi, T.M.; Sullivan, K.A.; Thomas, K.A. Purification and characterization of a naturally occurring vascular endothelial growth factor placenta growth factor heterodimer. J. Biol. Chem., 1995, 270(13), 7717-7723.
[http://dx.doi.org/10.1074/jbc.270.13.7717] [PMID: 7706320]
[45]
Senger, D.R.; Galli, S.J.; Dvorak, A.M.; Perruzzi, C.A.; Harvey, V.S.; Dvorak, H.F. Tumor cells secrete a vascular permeability factor that promotes accumulation of ascites fluid. Science, 1983, 219(4587), 983-985.
[http://dx.doi.org/10.1126/science.6823562] [PMID: 6823562]
[46]
Ferrara, N. VEGF and the quest for tumour angiogenesis factors. Nat. Rev. Cancer, 2002, 2(10), 795-803.
[http://dx.doi.org/10.1038/nrc909] [PMID: 12360282]

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