Novel Benzyloxyphenyl Pyrimidine-5-Carbonitrile Derivatives as Potential Apoptotic
Antiproliferative Agents

Amany       AL-Mahmoudy; Alaa       Hassan; Tarek       Ibrahim; Baha   G.M.   Youssif; Ehab       Taher; Mohamed       Tantawy; Eatedal       Abdel-Aal; Nermine       Osman

doi:10.2174/1871520621666210612043812

Abstract

Background: Pyrimidine-5-carbonitrile has a broad spectrum of biological activities such as antiviral, antioxidant, and anticancer activities. Among similar compounds, monastrol is the most prominent cell-permeant inhibitor of mitosis; therefore, we investigated the new Pyrimidine-5-carbonitrile as a cytotoxic agent for the p53 pathway.

Objective: Several new benzyloxyphenyl pyrimidine-5-carbonitrile derivatives were designed, synthesized, and characterized, and their cytotoxicity was evaluated. The most active compounds were tested for their activity against p53 as a mechanistic target for antiproliferative action.

Methods: The key intermediate tetrahydropyrimidine-5-carbonitrile derivative 4 was prepared by a multicomponent reaction (MCR) of the Biginelli type. S-alkylation of the key intermediate with the required alkyl or aralkyl halides or refluxing 4 with POCl3 followed by an amino acid yielded the target compounds. The cytotoxicity of 5c-e, 7a-c, 9, 10a, b, and 11 was evaluated using the A549 cell line of human lung adenocarcinoma, HepG2 liver cell line, and MDAMB- 231 cell line of breast cancer using the MTT assay. The transcription effects of 7a, 7c, and 11 on the p53 were assessed and compared with the reference doxorubicin.

Results: Compounds 7a, 7c, and 11 have the highest cytotoxic effect when applied to most cancer cells. The tested compounds with 5-FU showed a significant increase in the anticancer activity more than 5-FU alone. Compounds 7a, 7c, and 11 increased the level of active caspase 3 by 4-6-fold compared to untreated control cells in the human liver cancer cell line (HepG2). Compounds 7a, 7c, and 11 increased the levels of caspase 8 and 9, indicating activation of both intrinsic and extrinsic pathways and showing potent induction of Bax, down-regulation of Bcl-2 protein levels, and over-expression of Cytochrome C levels in HepG2 cell lines. Compound 11 exhibited cell cycle arrest at the Pre- G1 and G2/M phases in the cell cycle analysis of the HepG2 cell line. The results revealed an increase of 12.40-19.10 in p53 level compared to the test cells and that p53 protein level of 7a, 7c, and 11 was significantly inductive (636, 861, and 987 pg/mL, respectively) in relation to doxorubicin (1263 pg/mL).

Conclusion: Pyrimidine-5-carbonitrile derivatives have potent apoptotic and antiproliferative properties.

Keywords: Dihydropyrimidinone, antiproliferative, caspases, cytochrome c, BAX, p53.

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[1] 
Biginelli, P. Aldehyde-urea derivatives of aceto- and oxaloacetic acids. Gazz. Chim. Ital.,  1893, 23, 360-413.
[2] 
Kaur, R.; Chaudhary, S.; Kumar, K.; Gupta, M.K.; Rawal, R.K. Recent synthetic and medicinal perspectives of dihydropyrimidinones: A review. Eur. J. Med. Chem.,  2017, 132, 108-134.
[http://dx.doi.org/10.1016/j.ejmech.2017.03.025] [PMID:  28342939] 
[3] 
Naidu, B.N.; Sorenson, M.E.; Patel, M.; Ueda, Y.; Banville, J.; Beaulieu, F.; Bollini, S.; Dicker, I.B.; Higley, H.; Lin, Z.; Pajor, L.; Parker, D.D.; Terry, B.J.; Zheng, M.; Martel, A.; Meanwell, N.A.; Krystal, M.; Walker, M.A. Synthesis and evaluation of C2-carbon-linked heterocyclic-5-hydroxy-6-oxo-dihydropyrimidine-4-carboxamides as HIV-1 integrase inhibitors. Bioorg. Med. Chem. Lett.,  2015, 25(3), 717-720.
[http://dx.doi.org/10.1016/j.bmcl.2014.11.060] [PMID:  25529736] 
[4] 
de Vasconcelos, A.; Oliveira, P.S.; Ritter, M.; Freitag, R.A.; Romano, R.L.; Quina, F.H.; Pizzuti, L.; Pereira, C.M.P.; Stefanello, F.M.; Barschak, A.G. Antioxidant capacity and environmentally friendly synthesis of dihydropyrimidin-(2H)-ones promoted by naturally occurring organic acids. J. Biochem. Mol. Toxicol.,  2012, 26(4), 155-161.
[http://dx.doi.org/10.1002/jbt.20424] [PMID:  22447704] 
[5] 
Stefani, H.A.; Oliveira, C.B.; Almeida, R.B.; Pereira, C.M.P.; Braga, R.C.; Cella, R.; Borges, V.C.; Savegnago, L.; Nogueira, C.W. Dihydropyrimidin-(2H)-ones obtained by ultrasound irradiation: A new class of potential antioxidant agents. Eur. J. Med. Chem.,  2006, 41(4), 513-518.
[http://dx.doi.org/10.1016/j.ejmech.2006.01.007] [PMID:  16516351] 
[6] 
Mayer, T.U.; Kapoor, T.M.; Haggarty, S.J.; King, R.W.; Schreiber, S.L.; Mitchison, T.J. Small molecule inhibitor of mitotic spindle bipolarity identified in a phenotype-based screen. Science,  1999, 286(5441), 971-974.
[http://dx.doi.org/10.1126/science.286.5441.971] [PMID:  10542155] 
[7] 
Russowsky, D.; Canto, R.F.S.; Sanches, S.A.A.; D’Oca, M.G.M.; de Fátima, A.; Pilli, R.A.; Kohn, L.K.; Antônio, M.A.; de Carvalho, J.E. Synthesis and differential antiproliferative activity of Biginelli compounds against cancer cell lines: Monastrol, oxo-monastrol and oxygenated analogues. Bioorg. Chem.,  2006, 34(4), 173-182.
[http://dx.doi.org/10.1016/j.bioorg.2006.04.003] [PMID:  16765411] 
[8] 
Gartner, M.; Sunder-Plassmann, N.; Seiler, J.; Utz, M.; Vernos, I.; Surrey, T.; Giannis, A. Development and biological evaluation of potent and specific inhibitors of mitotic Kinesin Eg5. ChemBioChem,  2005, 6(7), 1173-1177.
[http://dx.doi.org/10.1002/cbic.200500005] [PMID:  15912555] 
[9] 
Kaur, N.; Kaur, K.; Raj, T.; Kaur, G.; Singh, A.; Aree, T.; Park, S.J.; Kim, T.J.; Singh, N.; Jang, D.O. One-pot synthesis of tricyclic dihydropyrimidine derivatives and their biological evaluation. Tetrahedron,  2015, 71, 332-337.
[http://dx.doi.org/10.1016/j.tet.2014.11.039] 
[10] 
Ragab, F.A.F.; Abou-Seri, S.M.; Abdel-Aziz, S.A.; Alfayomy, A.M.; Aboelmagd, M. Design, synthesis and anticancer activity of new monastrol analogues bearing 1,3,4-oxadiazole moiety. Eur. J. Med. Chem.,  2017, 138, 140-151.
[http://dx.doi.org/10.1016/j.ejmech.2017.06.026] [PMID:  28667871] 
[11] 
Skehan, P.; Storeng, R.; Scudiero, D.; Monks, A.; McMahon, J.; Vistica, D.; Warren, J.T.; Bokesch, H.; Kenney, S.; Boyd, M.R. New colorimetric cytotoxicity assay for anticancer-drug screening. J. Natl. Cancer Inst.,  1990, 82(13), 1107-1112.
[http://dx.doi.org/10.1093/jnci/82.13.1107] [PMID:  2359136] 
[12] 
Martins, P.; Jesus, J.; Santos, S.; Raposo, L.R.; Roma-Rodrigues, C.; Baptista, P.V.; Fernandes, A.R. Heterocyclic anticancer compounds: Recent advances and the paradigm shift towards the use of nanomedicine’s tool box. Molecules,  2015, 20(9), 16852-16891.
[http://dx.doi.org/10.3390/molecules200916852] [PMID:  26389876] 
[13] 
Akhtar, J.; Khan, A.A.; Ali, Z.; Haider, R.; Shahar Yar, M. Structure-activity relationship (SAR) study and design strategies of nitrogen-containing heterocyclic moieties for their anticancer activities. Eur. J. Med. Chem.,  2017, 125, 143-189.
[http://dx.doi.org/10.1016/j.ejmech.2016.09.023] [PMID:  27662031] 
[14] 
Feldser, D.M.; Kostova, K.K.; Winslow, M.M.; Taylor, S.E.; Cashman, C.; Whittaker, C.A.; Sanchez-Rivera, F.J.; Resnick, R.; Bronson, R.; Hemann, M.T.; Jacks, T. Stage-specific sensitivity to p53 restoration during lung cancer progression. Nature,  2010, 468(7323), 572-575.
[http://dx.doi.org/10.1038/nature09535] [PMID:  21107428] 
[15] 
Duffy, M.J.; Synnott, N.C.; Crown, J. p53 in cancer: Ready for therapeutic targeting? Transl. Cancer Res.,  2016, 5, 627-631.
[http://dx.doi.org/10.21037/tcr.2016.11.45] 
[16] 
Levesque, A.A.; Eastman, A. p53-based cancer therapies: Is defective p53 the Achilles heel of the tumor? Carcinogenesis,  2007, 28(1), 13-20.
[http://dx.doi.org/10.1093/carcin/bgl214] [PMID:  17088261] 
[17] 
Lujambio, A.; Akkari, L.; Simon, J.; Grace, D.; Tschaharganeh, D.F.; Bolden, J.E.; Zhao, Z.; Thapar, V.; Joyce, J.A.; Krizhanovsky, V.; Lowe, S.W. Non-cell-autonomous tumor suppression by p53. Cell,  2013, 153(2), 449-460.
[http://dx.doi.org/10.1016/j.cell.2013.03.020] [PMID:  23562644] 
[18] 
Jiang, L.; Kon, N.; Li, T.; Wang, S.J.; Su, T.; Hibshoosh, H.; Baer, R.; Gu, W. Ferroptosis as a p53-mediated activity during tumour suppression. Nature,  2015, 520(7545), 57-62.
[http://dx.doi.org/10.1038/nature14344] [PMID:  25799988] 
[19] 
Maurya, D.K.; Nandakumar, N.; Devasagayam, T.P.A. Anticancer property of gallic acid in A549, a human lung adenocarcinoma cell line, and possible mechanisms. J. Clin. Biochem. Nutr.,  2011, 48(1), 85-90.
[http://dx.doi.org/10.3164/jcbn.11-004FR] [PMID:  21297918] 
[20] 
Ranganathan, S.; Halagowder, D.; Sivasithambaram, N.D. Quercetin suppresses twist to induce apoptosis in mcf-7 breast cancer cells. PLoS One,  2015, 10(10), e0141370.
[http://dx.doi.org/10.1371/journal.pone.0141370] [PMID:  26491966] 
[21] 
El-Far, M.; Elmegeed, G.A.; Eskander, E.F.; Rady, H.M.; Tantawy, M.A. Novel modified steroid derivatives of androstanolone as chemotherapeutic anti-cancer agents. Eur. J. Med. Chem.,  2009, 44(10), 3936-3946.
[http://dx.doi.org/10.1016/j.ejmech.2009.04.020] [PMID:  19447526] 
[22] 
Abou-Zied, H.A.; Youssif, B.G.M.; Mohamed, M.F.A.; Hayallah, A.M.; Abdel-Aziz, M. EGFR inhibitors and apoptotic inducers: Design, synthesis, anticancer activity and docking studies of novel xanthine derivatives carrying chalcone moiety as hybrid molecules. Bioorg. Chem.,  2019, 89, 102997.
[http://dx.doi.org/10.1016/j.bioorg.2019.102997] [PMID:  31136902] 
[23] 
Hisham, M.; Youssif, B.G.M.; Osman, E.E.A.; Hayallah, A.M.; Abdel-Aziz, M. Synthesis and biological evaluation of novel xanthine derivatives as potential apoptotic antitumor agents. Eur. J. Med. Chem.,  2019, 176, 117-128.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.015] [PMID:  31108261] 
[24] 
Abdelazeem, A.H.; El-Saadi, M.T.; Said, E.G.; Youssif, B.G.M.; Omar, H.A.; El-Moghazy, S.M. Novel diphenylthiazole derivatives with multi-target mechanism: Synthesis, docking study, anticancer and anti-inflammatory activities. Bioorg. Chem.,  2017, 75, 127-138.
[http://dx.doi.org/10.1016/j.bioorg.2017.09.009] [PMID:  28938224] 
[25] 
Youssif, B.G.M.; Abdelrahman, M.H.; Abdelazeem, A.H.; Abdelgawad, M.A.; Ibrahim, H.M.; Salem, O.I.A.; Mohamed, M.F.A.; Treambleau, L.; Bukhari, S.N.A. Design, synthesis, mechanistic and histopathological studies of small-molecules of novel indole-2-carboxamides and pyrazino[1,2-a]indol-1(2H)-ones as potential anticancer agents effecting the reactive oxygen species production. Eur. J. Med. Chem.,  2018, 146, 260-273.
[http://dx.doi.org/10.1016/j.ejmech.2018.01.042] [PMID:  29407956] 
[26] 
Youssif, B.G.M.; Mohamed, A.M.; Osman, E.E.A.; Abou-Ghadir, O.F.; Elnaggar, D.H.; Abdelrahman, M.H.; Treamblu, L.; Gomaa, H.A.M. 5-Chlorobenzofuran-2-carboxamides: From allosteric CB1 modulators to potential apoptotic antitumor agents. Eur. J. Med. Chem.,  2019, 177, 1-11.
[http://dx.doi.org/10.1016/j.ejmech.2019.05.040] [PMID:  31128433] 
[27] 
Abdelbaset, M.S.; Abdel-Aziz, M.; Abuo-Rahma, G.E.A.; Abdelrahman, M.H.; Ramadan, M.; Youssif, B.G.M. Novel quinoline derivatives carrying nitrones/oximes nitric oxide donors: Design, synthesis, antiproliferative and caspase-3 activation activities. Arch. Pharm. (Weinheim),  2019, 352(1), e1800270.
[PMID: 30500087 ] 
[28] 
Abdelbaset, M.S.; Abuo-Rahma, G.E.A.; Abdelrahman, M.H.; Ramadan, M.; Youssif, B.G.M.; Bukhari, S.N.A.; Mohamed, M.F.A.; Abdel-Aziz, M. Novel pyrrol-2(3H)-ones and pyridazin-3(2H)-ones carrying quinoline scaffold as anti-proliferative tubulin polymerization inhibitors. Bioorg. Chem.,  2018, 80, 151-163.
[http://dx.doi.org/10.1016/j.bioorg.2018.06.003] [PMID:  29920422] 
[29] 
Abdelrahman, M.H.; Aboraia, A.S.; Youssif, B.G.M.; Elsadek, B.E.M. Design, synthesis and pharmacophoric model building of new 3-alkoxymethyl/3-phenyl indole-2-carboxamides with potential antiproliferative activity. Chem. Biol. Drug Des.,  2017, 90(1), 64-82.
[http://dx.doi.org/10.1111/cbdd.12928] [PMID:  28019082] 
[30] 
Shaw, P.H. The role of p53 in cell cycle regulation. Pathol. Res. Pract.,  1996, 192(7), 669-675.
[http://dx.doi.org/10.1016/S0344-0338(96)80088-4] [PMID:  8880867] 
[31] 
Chaudhary, A.S.; Jin, J.; Chen, W.; Tai, P.C.; Wang, B. Design, syntheses and evaluation of 4-oxo-5-cyano thiouracils as SecA inhibitors. Bioorg. Med. Chem.,  2015, 23(1), 105-117.
[http://dx.doi.org/10.1016/j.bmc.2014.11.017] [PMID:  25498235] 
[32] 
Nguyen, T.; Li, J.X.; Thomas, B.F.; Wiley, J.L.; Kenakin, T.P.; Zhang, Y. Allosteric modulation: An alternate approach targeting the cannabinoid cb1 receptor. Med. Res. Rev.,  2017, 37(3), 441-474.
[http://dx.doi.org/10.1002/med.21418] [PMID:  27879006] 
[33] 
Cohen, G.M. Caspases: The executioners of apoptosis. Biochem. J.,  1997, 326(Pt 1), 1-16.
[http://dx.doi.org/10.1042/bj3260001] [PMID:  9337844] 
[34] 
Slee, E.A.; Adrain, C.; Martin, S.J. Executioner caspase-3, -6, and - 7 perform distinct, non-redundant roles during the demolition phase of apoptosis. J. Biol. Chem.,  2001, 276(10), 7320-7326.
[http://dx.doi.org/10.1074/jbc.M008363200] [PMID: 11058599] 

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DOI https://dx.doi.org/10.2174/1871520621666210612043812	Print ISSN 1871-5206
Publisher Name Bentham Science Publisher	Online ISSN 1875-5992

Anti-Cancer Agents in Medicinal Chemistry

Novel Benzyloxyphenyl Pyrimidine-5-Carbonitrile Derivatives as Potential Apoptotic Antiproliferative Agents

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