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Medicinal Chemistry

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

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Research Article

Anti-proliferative Effects of Chromones: Potent Derivatives Affecting Cell Growth and Apoptosis in Breast, Bone-marrow and Cervical Cancer Cells

Author(s): Syeda Abida Ejaz, Mariia Miliutina, Peter Langer, Aamer Saeed* and Jamshed Iqbal*

Volume 15, Issue 8, 2019

Page: [883 - 891] Pages: 9

DOI: 10.2174/1573406415666190621155843

Price: $65

Abstract

Background: Previously, we have identified 3,3′–carbonyl–bis(chromones) (1a-h, 5e) and 3–(5–(benzylideneamino)thiozol–3–yl)–2H–chromen–2–ones (7a-j) as potent inhibitors of tissue non-specific alkaline phosphatase (TNAP). The present study was designed to investigate the cytotoxic and pro-apoptotic effect of the said derivatives.

Methods: The anti-proliferative effect of the derivatives was investigated in three cancer cell lines i.e., MCF-7, K-562, HeLa and normal BHK21 cells using MTT assay. The pro-apoptotic effect of the most potent derivatives was investigated by using flow cytometry, DAPI and PI staining and DNA binding studies.

Results: Among all the screened compounds, 1f, 1d, 1c (from 3,3′–carbonyl–bis(chromones), 7c, 7h and 7i (from 3–(5–(benzylideneamino)thiozol–3–yl)–2H–chromen–2–ones) exhibited remarkable growth inhibitory effects. Compounds 1f and 7c were found to be the most potent cytotoxic derivatives against MCF-7; 1d and 7h inhibited most of the proliferation of K-562 cells, whereas 1c and 7i showed maximum growth inhibition in HeLa cells. The identified compounds exerted lower micromolar potency against the respective cell line with significant selectivity over the normal cells (BHK–21). The identified compounds also induced either G2 or S-phase arrest within the respective cancer cells, chromatin condensation and nuclear fragmentation, as well as maximum interaction with DNA.

Conclusions: These results provide evidence that the characteristic chemical features of attached groups are the key factors for their anticancer effects and play a useful role in revealing the mechanisms of action in relation to the known compounds in future research programs.

Keywords: Alkaline phosphatase, breast cancer cells (MCF–7), bone marrow cells, cervical cancer cells (HeLa), anti-cancer effect, cell-cycle arrest.

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[1]
Burnstock, G.; Di Virgilio, F. Purinergic signalling and cancer. Purinergic Signal., 2013, 9(4), 491-540.
[http://dx.doi.org/10.1007/s11302-013-9372-5] [PMID: 23797685]
[2]
Hammerich, K.H.; Donahue, T.F.; Rosner, I.L.; Cullen, J.; Kuo, H.C.; Hurwitz, L.; Chen, Y.; Bernstein, M.; Coleman, J.; Danila, D.C.; Metwalli, A.R. Alkaline phosphatase velocity predicts overall survival and bone metastasis in patients with castration-resistant prostate cancer. Urol. Oncol., 2017, 35(7), 460.e21-460.e28.
[http://dx.doi.org/10.1016/j.urolonc.2017.02.001] [PMID: 28410987]
[3]
Rao, S.R.; Snaith, A.E.; Marino, D.; Cheng, X.; Lwin, S.T.; Orriss, I.R.; Hamdy, F.C.; Edwards, C.M. Tumour-derived alkaline phospha-tase regulates tumour growth, epithelial plasticity and disease-free survival in metastatic prostate cancer. Br. J. Cancer, 2017, 116(2), 227-236.
[http://dx.doi.org/10.1038/bjc.2016.402] [PMID: 28006818]
[4]
Kumar, S.K.; Hager, E.; Pettit, C.; Gurulingappa, H.; Davidson, N.E.; Khan, S.R. Design, synthesis, and evaluation of novel boronic-chalcone derivatives as antitumor agents. J. Med. Chem., 2003, 46(14), 2813-2815.
[http://dx.doi.org/10.1021/jm030213+] [PMID: 12825923]
[5]
Ellis, G.P. The chemistry of heterocyclic compounds, chromenes, chromanones, and chromones; John Wiley & Sons, 2008.
[6]
Costantino, L.; Barlocco, D. Privileged structures as leads in medicinal chemistry. Curr. Med. Chem., 2006, 13(1), 65-85.
[http://dx.doi.org/10.2174/092986706775197999] [PMID: 16457640]
[7]
Raj, T.; Bhatia, R.K.; Kapur, A.; Sharma, M.; Saxena, A.K.; Ishar, M.P. Cytotoxic activity of 3-(5-phenyl-3H-[1,2,4]dithiazol-3-yl)chromen-4-ones and 4-oxo-4H-chromene-3-carbothioic acid N-phenylamides. Eur. J. Med. Chem., 2010, 45(2), 790-794.
[http://dx.doi.org/10.1016/j.ejmech.2009.11.001] [PMID: 19939522]
[8]
Ghate, M.; Kusanur, R.A.; Kulkarni, M.V. Synthesis and in vivo analgesic and anti-inflammatory activity of some bi heterocyclic couma-rin derivatives. Eur. J. Med. Chem., 2005, 40(9), 882-887.
[http://dx.doi.org/10.1016/j.ejmech.2005.03.025] [PMID: 16140424]
[9]
Yang, L.; Qiao, L.; Xie, D.; Yuan, Y.; Chen, N.; Dai, J.; Guo, S. 2-(2-phenylethyl)chromones from Chinese eaglewood. Phytochemistry, 2012, 76, 92-97.
[http://dx.doi.org/10.1016/j.phytochem.2011.11.017] [PMID: 22243963]
[10]
Frum, Y.; Viljoen, A.M. In vitro 5-lipoxygenase and anti-oxidant activities of South African medicinal plants commonly used topically for skin diseases. Skin Pharmacol. Physiol., 2006, 19(6), 329-335.
[http://dx.doi.org/10.1159/000095253] [PMID: 16931900]
[11]
Keri, R.S.; Budagumpi, S.; Pai, R.K.; Balakrishna, R.G. Chromones as a privileged scaffold in drug discovery: a review. Eur. J. Med. Chem., 2014, 78, 340-374.
[http://dx.doi.org/10.1016/j.ejmech.2014.03.047] [PMID: 24691058]
[12]
Miliutina, M.; Ejaz, S.A.; Iaroshenko, V.O.; Villinger, A.; Iqbal, J.; Langer, P. Synthesis of 3,3′-carbonyl-bis(chromones) and their activity as mammalian alkaline phosphatase inhibitors. Org. Biomol. Chem., 2016, 14(2), 495-502.
[http://dx.doi.org/10.1039/C5OB01350J] [PMID: 26490672]
[13]
Saeed, A.; Ejaz, S.A.; Shehzad, M.; Hassan, S.; al-Rashida, M.; Lecka, J.; Sevigny, J.; Iqbal, J. 3-(5-(Benzylideneamino)thiazol-3-yl)-2H-chromen-2-ones: A new class of alkaline phosphatase and ecto-5[prime or minute]-nucleotidase inhibitors. RSC Advances, 2016, 6, 21026-21036.
[http://dx.doi.org/10.1039/C5RA24684A]
[14]
Hassan, S.; Ejaz, S.A.; Saeed, A.; Shehzad, M.; Ullah Khan, S.; Lecka, J.; Sévigny, J.; Shabir, G.; Iqbal, J. 4-Aminopyridine based amide derivatives as dual inhibitors of tissue non-specific alkaline phosphatase and ecto-5′-nucleotidase with potential anticancer activity. Bioorg. Chem., 2018, 76, 237-248.
[http://dx.doi.org/10.1016/j.bioorg.2017.11.013] [PMID: 29197225]
[15]
Saito, Y.; Uchida, N.; Tanaka, S.; Suzuki, N.; Tomizawa-Murasawa, M.; Sone, A.; Najima, Y.; Takagi, S.; Aoki, Y.; Wake, A.; Taniguchi, S.; Shultz, L.D.; Ishikawa, F. Induction of cell cycle entry eliminates human leukemia stem cells in a mouse model of AML. Nat. Biotechnol., 2010, 28(3), 275-280.
[http://dx.doi.org/10.1038/nbt.1607] [PMID: 20160717]
[16]
Lin, G.J.; Jiang, G.B.; Xie, Y.Y.; Huang, H.L.; Liang, Z.H.; Liu, Y.J. Cytotoxicity, apoptosis, cell cycle arrest, reactive oxygen species, mitochondrial membrane potential, and Western blotting analysis of ruthenium(II) complexes. J. Biol. Inorg. Chem., 2013, 18(8), 873-882.
[http://dx.doi.org/10.1007/s00775-013-1032-2] [PMID: 23989405]
[17]
Sirajuddin, M.; Ali, S.; McKee, V.; Zaib, S.; Iqbal, J. Organ-otin(iv) carboxylate derivatives as a new addition to anti-cancer and antileish-manial agents: Design, physicochemical characterization and interaction with Salmon sperm DNA. RSC Advances, 2014, 4, 57505-57521.
[http://dx.doi.org/10.1039/C4RA10487K]
[18]
Farahat, A.A.; Kumar, A.; Say, M.; Wenzler, T.; Brun, R.; Paul, A.; Wilson, W.D.; Boykin, D.W. Exploration of DAPI analogues: Synthe-sis, antitrypanosomal activity, DNA binding and fluorescence properties. Eur. J. Med. Chem., 2017, 128, 70-78.
[http://dx.doi.org/10.1016/j.ejmech.2017.01.037] [PMID: 28152428]
[19]
Mirza, M.B.; Elkady, A.I.; Al-Attar, A.M.; Syed, F.Q.; Mohammed, F.A.; Hakeem, K.R. Induction of apoptosis and cell cycle arrest by ethyl acetate fraction of Phoenix dactylifera L. (Ajwa dates) in prostate cancer cells. J. Ethnopharmacol., 2018, 218, 35-44.
[http://dx.doi.org/10.1016/j.jep.2018.02.030] [PMID: 29476962]
[20]
Pietkiewicz, S.; Schmidt, J.H.; Lavrik, I.N. Quantification of apoptosis and necroptosis at the single cell level by a combination of Imaging Flow Cytometry with classical Annexin V/propidium iodide staining. J. Immunol. Methods, 2015, 423, 99-103.
[http://dx.doi.org/10.1016/j.jim.2015.04.025] [PMID: 25975759]

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