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Medicinal Chemistry


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

Research Article

ZnO Nanoparticles Catalyst in the Synthesis of Bioactive Fused Pyrimidines as Anti-breast Cancer Agents Targeting VEGFR-2

Author(s): Dina H. Dawood, Eman M.H. Abbas, Thoraya A. Farghaly*, Mamdouh M. Ali and Mohammed F. Ibrahim

Volume 15, Issue 3, 2019

Page: [277 - 286] Pages: 10

DOI: 10.2174/1573406414666180912113226

Price: $65


Background: Pyrimidines emerged as a remarkable class of heterocyclic compounds that have reinforced the pharmaceutical chemistry with various bioactive antitumor agents. Moreover, pyrimidine scaffold displayed VEGFR-2 inhibitory activity. Also, nano-sized catalysts are used in organic reactions in order to speed up the catalytic process.

Objective: We were interested herein to synthesize a new series of fused pyrimidines using ZnO(NPs) to investigate their antitumor efficiency against breast MCF7 cancer and their VEGFR- 2 inhibition properties.

Method: A simple and efficient method for the synthesis of fused pyrimidines was developed using zinc oxide nanoparticles ZnO(NPs) in refluxing ethanol.

Results: The proposed structures of all new fused pyrimidines are in agreement with their spectral data. Antitumor evaluation of newly fused pyrimidine derivatives against breast MCF-7 cancer was performed. It was apparent that the 2-phenylpyrazolo[1,5-a]pyrimidine derivatives 9a (IC50 = 9.12±1.16 µg/ml), 9c (IC50 = 9.10±1.07 µg/ml) and 9d (IC50 = 9.60±1.22 µg/ml) exhibited equipotent antitumor activity as Tamoxifen (IC50 = 9.11±0.90 µg/ml). Also, the inhibitory activity of the novel fused pyrimidine derivatives on VEGFR-2 as well as Tamoxifen was determined using breast cancer cell line MCF-7. The data was obvious that 2-phenylpyrazolo[1,5-a]pyrimidine derivatives 9a, 9c and 9d exhibited noticeable VEGFR-2 inhibitory effect with % inhibition ranging from 80-84 % versus Tamoxifen 93.5%.

Conclusion: We succeeded in this context to synthesize new fused pyrimidines using ZnO(NPs) as anti-breast cancer agents targeting VEGFR-2.

Keywords: ZnO(NPs), fused pyrimidines, anti-breast cancer, catalyst, VEGFR-2 inhibitory effect, heteroamines.

Graphical Abstract
Ali, I.; Haque, A.; Saleem, K.; Hsieh, M. Curcumin-I Knoevenagel’s condensates and their Schiff’s bases as anticancer agents: synthesis, pharmacological and simulation studies. Bioorg. Med. Chem., 2013, 21, 3808-3820.
Altmann, K.H. Microtubule-stabilizing agents: A growing class of important anticancer drugs. Curr. Opin. Chem. Biol., 2001, 5, 424-431.
Eckhardt, S. Recent progress in the development of anticancer agents. Curr. Med. Chem. Anticancer Agents, 2002, 2, 419-439.
Wartmann, M.; Altmann, K.H. The biology and medicinal chemistry of epothilones. Curr. Med. Chem. Anticancer Agents, 2002, 2, 1231-1248.
Bridges, E.M.; Harris, A.L. The angiogenic process as a therapeutic target in cancer. Biochem. Pharmacol., 2011, 81, 1183-1191.
Gerhardt, H. VEGF and endothelial guidance in angiogenic sprouting. Organogenesis, 2008, 4, 241-246.
Shibuya, M.; Claesson-Welsh, L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res., 2006, 312, 549-560.
Nguyen, T.L. Targeting RSK: An overview of small molecule inhibitors. Anticancer. Agents Med. Chem., 2008, 8, 710-716.
Abdel-Mohsen, H.T.; Ragab, F.A.; Ramla, M.M.; El Diwani, H.I. Novel benzoimidazole-pyrimidine conjugates as potential antitumor agents. Eur. J. Med. Chem., 2010, 45, 2336-2344.
He, H.Y.; Zhao, J.N.; Jia, R.; Zhao, Y.L.; Yang, S.Y.; Yu, L.T.; Yang, L. Novel Pyrazolo [3,4-d]pyrimidine derivatives as potential anti-tumor agents: Exploratory synthesis, preliminary structure-activity relationships, and in Vitro biological evaluation. Molecules, 2011, 16, 10685-10694.
Kandeel, M.M.; Ali, S.M.; Abed El, A.L.L. E.K.; Abdelgawad, M.A.; Lamie, P.F. Synthesis and antitumor activity of novel pyrazolo [3,4-d] pyrimidines. Der. Pharm. Chemica., 2012, 4(4), 1704-1715.
Hafez, T.S.; Osman, S.A.; Yosef, H.A.; Abdel-all, A.S.; Hassan, A.S. EL-sawy, A.A.; Abdallah, M.M.; Youns, M. Structural elucidation and in vitro antitumor activities of some pyrazolopyrimidines and schiff bases derived from 5-Amino-3-(arylamino)-1H-pyrazole-4-carboxamides. Sci. Pharm., 2013, 81, 339-357.
Ahmed, S.A.; Ahmed, O.M.; Elgendy, H.S. Novel synthesis of puriens analougues and thieno [2,3-b] pyridine derivatives with anticancer and antioxidant activity. J. Pharm. Res., 2014, 8(9), 1303-1313.
Mohamed, A.M.; Al-Qalawi, H.R.; El-Sayed, W.A.; Arafa, W.A. ALhumaimess, M.S.; Hassan, A.K. Anticancer activity of newly synthe-sized triazolopyrimidine derivatives and their nucleoside analogs. Acta Poloniae Pharmaceut. Drug Res., 2015, 72(2), 307-318.
Abdel-latif, E.; Abdel-fattah, S.; Gaffer, H.E.; Etman, H.A. Synthesis and anti- tumor activity of some new pyrazolo [3,4-d]pyrimidine and pyrazolo [3,4-b] pyridine derivatives. Egyp. J. Basic Appl. Sci., 2016, 3, 118-124.
Sloan, B.; Scheinfeld, N.S. Pazopanib, a VEGF receptor tyrosine kinase inhibitor for cancer therapy. Curr. Opin. Investig. Drugs, 2008, 9(12), 1324-1335.
Hao, J.; Ho, J.N.; Lewis, J.A.; Karim, K.A.; Daniels, R.N.; Gentry, P.R.; Hopkins, C.R.; Lindsley, C.W.; Hong, C.C. In vivo structure-activity relationship study of Dorsomorphin analogues identifies selective VEGF and BMP inhibitors. ACS Chem. Biol., 2010, 5(2), 245-253.
Farghaly, T.A.; Dawood, K.M.; Shaaban, M.R. Chemistry and biological activity of pyridotriazolopyrimidines (Review). Curr. Org. Synth., 2015, 12(3), 230-260.
Qingyun, R.; Xiaosong, T.; Hongwu, H. Efficient synthesis of fused pyrimidine derivatives with biological activity via aza-wittig reaction. Curr. Org. Synth., 2011, 8, 752-763.
Gomha, S.M.; Farghaly, T.A.; Mabkhot, Y.N.; Zayed, M.E.M.; Mohamed, A.M.G. Microwave-assisted synthesis of some novel azoles and azolopyrimidines as antimicrobial agents. Molecules, 2017, 22(3), 346-355.
Sapkal, S.B.; Shelke, K.F.; Shingate, B.B.; Shingare, M.S. Nickel nanoparticle-catalyzed facile and efficient one-pot synthesis of polyhy-droquinoline derivatives via Hantzsch condensation under solvent-free conditions. Tetrahedron Lett., 2009, 50(15), 1754-1756.
Banerjee, S.; Payra, S.; Saha, A.; Sereda, G. ZnO nanoparticles: a green efficient catalyst for the room temperature synthesis of biologically active 2-aryl-1,3-benzothiazole and 1,3-benzoxazole derivatives. Tetrahedron Lett., 2014, 55, 5515-5520.
MaGee. D.I.; Dabiri, M.; Salehi, P.; Torkian, L. Highly efficient one-pot three-component Mannich reaction catalyzed by ZnO-nanoparticles in water. ARKIVOC, 2011, 11, 156-164.
Safaei-Ghomi, J.; Ghasemzadeh, M.A.; Zahedi, S. ZnO Nanoparticles: A Highly Effective and Readily Recyclable Catalyst for the One-Pot Synthesis of 1,8-dioxo-decahydroacridine and 1,8-dioxooctahydro-xanthene Derivatives. J. Mex. Chem. Soc., 2013, 57(1), 1-7.
Elsharabasy, F.S.; Gomha, S.M.; Farghaly, T.A.; Elzahabi, H.S.A. An efficient synthesis of novel bioactive thiazolyl-phthalazinediones under ultrasound irradiation. Molecules, 2017, 22, 319-332.
Awad, H.M.; Fayad, W.; El-Hallouty, S.M.; Farghaly, T.A.; Abdallah, M.M. Anticancer activity of some [1,2,4]Triazepino [2,3-a]quinazoline derivatives: monolayer and multicellular spheroids in vitro models. Med. Chem. Res., 2016, 25(9), 1952-1957.
Farghaly, T.A.; Abdallah, M.A.; Muhammad, Z.A. 2,7-Diarylidene- cycloheptanone, Hydrazonoyl chlorides and heterocyclic amines as precursors for synthesis of bioactive new fused cycloheptapyrimidine derivatives. Curr. Org. Synth., 2016, 13, 291-299.
Dawood, D.H.; Jasass, R.S.; Amin, M.M.; Farghaly, T.A.; Abbas, E.M.H. Synthesis of some new azoloazines with potent Anti-inflammatory and analgesic activity. J. Heterocycl. Chem., 2017, 54(2), 1578-1589.
Abbas, E.M.H.; Dawood, D.H.; Farghaly, T.A.; El-hag, F.A.; Ali, M.M. Synthesis and structure activity relationship study of novel pyra-zolylthiazoles as potential anti-breast cancer agents. J. Heterocycl. Chem., 2017, 54(3), 1974-1982.
Dawood, D.H.; Batran, R.Z.; Farghaly, T.A.; Khedr, M.A.; Abdulla, M.M. New Coumarin Derivatives as Potent Selective COX-2 Inhibi-tors; Synthesis, Anti-inflammatory, QSAR and Molecular Modeling Studies. Arch. Pharm. Chem. Life Sci., 2015, 348(12), 875-888.
Farghaly, T.A.; Abdallah, M.A.; Masaret, G.S.; Muhammad, Z.A. New and efficient approach for synthesis of novel bioactive [1,3,4] thia-diazoles incorporated with1,3-thiazole moiety. Eur. J. Med. Chem., 2015, 97, 320-333.
Farghaly, T.A.; Abbas, E.M.H.; Dawood, K.M.; El-Naggar, T.B.A. Synthesis of 2-phenylazonaptho [1,8-ef][1,4]diazepines and 9-3-(arylhydrazono)pyrrolo [1,2-a]perimidines as antitumor agents. Molecules, 2014, 19, 740-755.
Safaei-Ghomi, J. Ghasemzadeh. M.A. Zinc oxide nanoparticles: A highly efficient and readily recyclable catalyst for the synthesis of Xanthenes. Chin. Chem. Lett., 2012, 23(11), 1225-1229.
Desenko, S.M.; Orlov, V.D.; Shishkin, O.V.; Barykin, K.E.; Linderman, S.V.; Struchkov, Yu.T. Imine-enamine tautomerism of dihydra-zolopyrimidines 5. Steric effects and the tautomeric equilibrium for dihrdro-1,2,4-triazolo [1,5-a] pyrimidines. Chem. Heterocycl. Chem., 1993, 29, 1163-1168.
Lipson, V.V.; Desenko, S.M.; Shishkina, S.V.; Shirobokova, M.G.; Shishkin, O.V.; Orlov, V.D. Cyclocondensation of 2-aminobenzo-imidazole with dimedone and its arylidene derivatives. Chem. Heterocycl. Compd., 2003, 39, 1041-1047.
EL-Rayyes. N.; AL-Johary, A. Hererocycles. 7 synthesis of new pyrazoline. J. Chem. Eng. Data, 1985, 30, 500-502.
Mishra, L.; Sinha, R. Synthesis, characterization, luminescent and redox properties of some mononuclear and dinuclear ruthenium (II) polypyridyl complexes. Indian J. Chem., 2000, 39A, 1295-1300.
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New color-imetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst., 1990, 82, 1107-1112.

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