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Medicinal Chemistry

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ISSN (Print): 1573-4064
ISSN (Online): 1875-6638

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Research Article

Synthesis and Cytotoxicity Evaluation of Novel Indole Derivatives as Potential Anti-Cancer Agents

Author(s): Mona M. Kamel, Mohamed K. Abdel-hameid, Hala B. El-Nassan* and Eman A. El-Khouly

Volume 15, Issue 8, 2019

Page: [873 - 882] Pages: 10

DOI: 10.2174/1573406415666190408125514

Price: $65

Abstract

Background: Marine sponges and tunicates have been a wealthy source of cytotoxic compounds such as indole alkaloids. Most of the indole alkaloids show in vitro cytotoxic and antineoplastic activities against a wide range of cancer cell lines.

Objective: Three series of bioisosteres of marine indole alkaloids (meridianins) were synthesized and the compounds were tested for their in vitro anti-proliferative activity against HCT-116 cellline. In the design of the targeted analogues, the 2-aminopyrimidine ring of merdianins was replaced with 5-aminopyrazole, pyrazolo[1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings.

Results: The cytotoxic screening of the synthesized compounds revealed that pyrazolo[1,5- a]pyrimidines (compounds 9c and 11a) had the most potent cytotoxic activity with IC50 = 0.31 μM and 0.34 μM respectively. Compounds 9c and 11a were further investigated for their kinase inhibitory potencies toward six kinases (CDK5/p25, CK1ð/ε, GSK-3α/β, Dyrk1A, Erk2, and CLK1). They exhibited effective inhibition of GSK-3α/β (IC50 = 0.196 μM and 0.246 μM, respectively) and Erk2 (IC50 = 0.295 μM and 0.376 μM, respectively).

Conclusion: Meridianins emerged as promising lead structures that need further development to obtain more selective and potent cytotoxic agents. One of these modifications involved the replacement of 2-aminopyrimidinyl ring of meridianins with other heterocyclic rings. Both pyrazolo[ 1,5-a]pyrimidine and pyrazolo[3,4-b]pyridine rings showed promising cytotoxic activity compared to the five membered 5-aminopyrazole.

Keywords: Indole, meridianins, cytotoxic activity, HCT-116 cell-line, GSK-3α/β, Erk2.

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[1]
Bray, F.; Ferlay, J.; Soerjomataram, I.; Siegel, R.L.; Torre, L.A.; Jemal, A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2018, 68(6), 394-424.
[http://dx.doi.org/10.3322/caac.21492] [PMID: 30207593]
[2]
Munro, M.H.G.; Blunt, J.W.; Dumdei, E.J.; Hickford, S.J.H.; Lill, R.E.; Li, S.; Battershill, C.N.; Duckworth, A.R. The dis-covery and development of marine compounds with pharma-ceutical potential. J. Biotechnol., 1999, 70(1-3), 15-25.
[http://dx.doi.org/10.1016/S0168-1656(99)00052-8] [PMID: 10412202]
[3]
Bharate, S.B.; Yadav, R.R.; Battula, S.; Vishwakarma, R.A. Meridianins: marine-derived potent kinase inhibitors. Mini Rev. Med. Chem., 2012, 12(7), 618-631.
[http://dx.doi.org/10.2174/138955712800626728] [PMID: 22512550]
[4]
Faulkner, D.J. Marine natural products. Nat. Prod. Rep., 2001, 18(1), 1-49.
[http://dx.doi.org/10.1039/b006897g] [PMID: 11245399]
[5]
Shaw, S.J.; Goff, D.A.; Lin, N.; Singh, R.; Li, W.; McLaughlin, J.; Baltgalvis, K.A.; Payan, D.G.; Kinsella, T.M. Developing DYRK inhibitors derived from the meridianins as a means of increasing levels of NFAT in the nucleus. Bioorg. Med. Chem. Lett., 2017, 27(11), 2617-2621.
[http://dx.doi.org/10.1016/j.bmcl.2017.03.037] [PMID: 28408219]
[6]
Yadav, R.R.; Sharma, S.; Joshi, P.; Wani, A.; Vishwakarma, R.A.; Kumar, A.; Bharate, S.B. Meridianin derivatives as po-tent Dyrk1A inhibitors and neuroprotective agents. Bioorg. Med. Chem. Lett., 2015, 25(15), 2948-2952.
[http://dx.doi.org/10.1016/j.bmcl.2015.05.034] [PMID: 26048785]
[7]
Giraud, F.; Alves, G.; Debiton, E.; Nauton, L.; Théry, V.; Durieu, E.; Ferandin, Y.; Lozach, O.; Meijer, L.; Anizon, F.; Pereira, E.; Moreau, P. Synthesis, protein kinase inhibitory potencies, and in vitro antiproliferative activities of merid-ianin derivatives. J. Med. Chem., 2011, 54(13), 4474-4489.
[http://dx.doi.org/10.1021/jm200464w] [PMID: 21623630]
[8]
Radwan, M.A.A.; El-Sherbiny, M. Synthesis and antitumor activity of indolylpyrimidines: marine natural product merid-ianin D analogues. Bioorg. Med. Chem., 2007, 15(3), 1206-1211.
[http://dx.doi.org/10.1016/j.bmc.2006.11.023] [PMID: 17157024]
[9]
Akue-Gedu, R.; Debiton, E.; Ferandin, Y.; Meijer, L.; Pru-dhomme, M.; Anizon, F.; Moreau, P. Synthesis and biological activities of aminopyrimidyl-indoles structurally related to meridianins. Bioorg. Med. Chem., 2009, 17(13), 4420-4424.
[http://dx.doi.org/10.1016/j.bmc.2009.05.017] [PMID: 19477650]
[10]
Yadav, R.R.; Khan, S.I.; Singh, S.; Khan, I.A.; Vishwakarma, R.A.; Bharate, S.B. Synthesis, antimalarial and antitubercular activities of meridianin derivatives. Eur. J. Med. Chem., 2015, 98, 160-169.
[http://dx.doi.org/10.1016/j.ejmech.2015.05.020] [PMID: 26005918]
[11]
Časar, Z.; Bevk, D.; Svete, J.; Stanovnik, B. Reaction of me-thyl (2E)-3-dimethylamino-2-(1H-indol-3-Yl)-propenoate with ureas: Facile entry into the polycyclic meridianin ana-logues with uracil structural unit. Tetrahedron, 2005, 61(31), 7508-7519.
[http://dx.doi.org/10.1016/j.tet.2005.05.075]
[12]
Jiang, B.; Xiong, X-N.; Yang, C-G. Synthesis and antitumor evaluation of novel monoindolyl-4-trifluoromethylpyridines and bisindolyl-4-trifluoromethylpyridines. Bioorg. Med. Chem. Lett., 2001, 11(4), 475-477.
[http://dx.doi.org/10.1016/S0960-894X(00)00704-6] [PMID: 11229751]
[13]
Jiang, B.; Yang, C-G.; Xiong, W-N.; Wang, J. Synthesis and cytotoxicity evaluation of novel indolylpyrimidines and in-dolylpyrazines as potential antitumor agents. Bioorg. Med. Chem., 2001, 9(5), 1149-1154.
[http://dx.doi.org/10.1016/S0968-0896(00)00337-0] [PMID: 11377173]
[14]
Xiong, W.N.; Yang, C.G.; Jiang, B. Synthesis of novel ana-logues of marine indole alkaloids: mono(indolyl)-4-trifluoromethylpyridines and bis(indolyl)-4-trifluoromethylpyridines as potential anticancer agents. Bioorg. Med. Chem., 2001, 9(7), 1773-1780.
[http://dx.doi.org/10.1016/S0968-0896(01)00070-0] [PMID: 11425579]
[15]
Slaett, J.; Romero, I.; Bergman, J. Cyanoacetylation of indoles, pyrroles and aromatic amines with the combination cyanoace-tic acid and acetic anhydride. Synth, 2004, 16, 2760-2765.
[16]
Ghiron, C.; Nencini, A.; Micco, I.; Zanaletti, R.; Maccari, L.; Bothmann, H.; Haydar, S.; Varrone, M.; Pratelli, C.; Harrison, B. Nicotinic acetylcholine receptor modulators . WO2008/87529 2008.
[17]
Borisova, I.A.; Zubarev, A.A.; Rodinovskaya, L.A.; Shesto-palov, A.M. Synthesis and physicochemical properties of Merocyanine dyes based on Dihydropyridine and fragments of Cyanoacetic acid derivatives. ARKIVOC, 2017, iii, 73-86.
[http://dx.doi.org/10.24820/ark.5550190.p009.908]
[18]
Huppatz, J.L. Systemic fungicides. The synthesis of certain pyrazole analogues of carboxin. Aust. J. Chem., 1983, 36(1), 135-147.
[http://dx.doi.org/10.1071/CH9830135]
[19]
Jones, R.G. Reactions of Orthoesters with active methylene compounds. J. Am. Chem. Soc., 1952, 74(19), 4889-4891.
[http://dx.doi.org/10.1021/ja01139a046]
[20]
McCall, M.A. Reactions of substituted methylenemalono-nitriles and their derivatives1. J. Org. Chem., 1962, 27(7), 2433-2439.
[http://dx.doi.org/10.1021/jo01054a036]
[21]
Gazit, A.; Yaish, P.; Gilon, C.; Levitzki, A.; Tyrphostins, I. Tyrphostins I: synthesis and biological activity of protein ty-rosine kinase inhibitors. J. Med. Chem., 1989, 32(10), 2344-2352.
[http://dx.doi.org/10.1021/jm00130a020] [PMID: 2552117]
[22]
Chen, X.; Chen, X.; Zhao, Z.; Lue, P.; Wang, Y. 2, 4-Dicyano-3-diethylamino-9, 9-diethylfluorene based blue light emitting star-shaped compounds: Synthesis and properties. Chin. J. Chem., 2009, 27(5), 971-977.
[http://dx.doi.org/10.1002/cjoc.200990165]
[23]
Angeletti, E.; Canepa, C.; Martinetti, G.; Venturello, P. Amino groups immobilized on silica gel: An efficient and reusable heterogeneous catalyst for the Knoevenagel condensation. J. Chem. Soc., Perkin Trans. 1, 1989, 1, 105-107.
[http://dx.doi.org/10.1039/p19890000105]
[24]
Takeuchi, H.; Baba, M.; Shigeta, S. An application of tetrazo-lium (MTT) colorimetric assay for the screening of anti-herpes simplex virus compounds. J. Virol. Methods, 1991, 33(1-2), 61-71.
[http://dx.doi.org/10.1016/0166-0934(91)90008-N] [PMID: 1658029]
[25]
Vistica, D.T.; Skehan, P.; Scudiero, D.; Monks, A.; Pittman, A.; Boyd, M.R. Tetrazolium-based assays for cellular viabil-ity: a critical examination of selected parameters affecting formazan production. Cancer Res., 1991, 51(10), 2515-2520.
[PMID: 2021931]
[26]
Denizot, F.; Lang, R. Rapid colorimetric assay for cell growth and survival. Modifications to the tetrazolium dye procedure giving improved sensitivity and reliability. J. Immunol. Methods, 1986, 89(2), 271-277.
[http://dx.doi.org/10.1016/0022-1759(86)90368-6] [PMID: 3486233]
[27]
Carmichael, J.; DeGraff, W.G.; Gazdar, A.F.; Minna, J.D.; Mitchell, J.B. Evaluation of a tetrazolium-based semiautomat-ed colorimetric assay: assessment of chemosensitivity testing. Cancer Res., 1987, 47(4), 936-942.
[PMID: 3802100]
[28]
Edmondson, J.M.; Armstrong, L.S.; Martinez, A.O. A rapid and simple MTT-based spectrophotometric assay for deter-mining drug sensitivity in monolayer cultures. J. Tissue Cult. Methods, 1988, 11(1), 15-17.
[http://dx.doi.org/10.1007/BF01404408]
[29]
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. J. Immunol. Methods, 1983, 65(1-2), 55-63.
[http://dx.doi.org/10.1016/0022-1759(83)90303-4] [PMID: 6606682]
[30]
Wang, Q.; Zhou, Y.; Wang, X.; Evers, B.M. Glycogen syn-thase kinase-3 is a negative regulator of extracellular signal-regulated kinase. Oncogene, 2006, 25(1), 43-50.
[http://dx.doi.org/10.1038/sj.onc.1209004] [PMID: 16278684]
[31]
Wang, Q.; Wang, X.; Hernandez, A.; Kim, S.; Evers, B.M. Inhibition of the phosphatidylinositol 3-kinase pathway con-tributes to HT29 and Caco-2 intestinal cell differentiation. Gastroenterology, 2001, 120(6), 1381-1392.
[http://dx.doi.org/10.1053/gast.2001.24044] [PMID: 11313308]
[32]
Ding, Q.; Wang, Q.; Evers, B.M. Alterations of MAPK activi-ties associated with intestinal cell differentiation. Biochem. Biophys. Res. Commun., 2001, 284(2), 282-288.
[http://dx.doi.org/10.1006/bbrc.2001.4969] [PMID: 11394874]

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