Cytotoxic Action of N-aryl, Furan-derived Aminophosphonates against HT29 and HCT116 Cancer Cell Lines

Author(s): Jarosław Lewkowski*, Edyta Rzeszotarska, Agnieszka Matusiak, Marta Morawska, Gabriela Gajek, Karolina Nowak, Renata Kontek*.

Journal Name: Anti-Cancer Agents in Medicinal Chemistry
(Formerly Current Medicinal Chemistry - Anti-Cancer Agents)

Volume 19 , Issue 4 , 2019

Become EABM
Become Reviewer

Graphical Abstract:


Background: The anticancer activity of aminophosphonic derivatives has been described extensively, some recent papers included furan-derived aminophosphonates and their cytostatic action against various cancer cells.

Objective: A series of twelve furan-derived dibenzyl and diphenyl aminophosphonates 2a-f and 3a-f was synthesized and tested in aspect of their cytotoxic action on two cell lines of colorectal cancer: HT29 and HCT116. Seven of them are new compounds, while the rest five have already been published by us, together with their cytotoxic action against squamous esophageal cancer cells.

Methods: To estimate the cytotoxicity effect of tested compounds MTT test was used. Pro-apoptotic activity of five selected compounds was evaluated using APC Annexin V Apoptosis Detection Kit on a flow cytometer. Quantification of caspases 3/7 activity was performed using Caspase-Glo® 3/7 Assay Kit.

Results: Five of these aminophosphonates showed significant cytotoxicity higher than those of cisplatin. Simultaneous evaluation of their cytotoxicity against PBLs revealed that these compounds are rather not harmful for regular human lymphocytes. Tests on apoptosis vs. their necrotic actions on cells were performed with selected compounds showing the most significant cytotoxicity against cancer cells and all tested compounds did not induce significant increase of necrosis in cells, whereas they showed moderate-to-strong proapoptotic actions even at the lowest applied concentration. Caspase 3/7 activity results confirmed proapoptotic properties of tested aminophosphonates.

Conclusion: From among studied compounds, dibenzyl N-phenyl substituted amino(2-furyl)methylphsophonates were found to be more potent compounds in aspect of their antiproliferative action than the corresponding diphenyl derivatives.

Keywords: Furan-derived aminophosphonates, cytotoxicity, colorectal cancer cells, apoptosis, caspase activity, antiproliferative.

Kafarski, P.; Lejczak, B. Biological activity of aminophosphonic acids. Phosphorus Sulfur Silicon Relat. Elem., 1991, 63, 193-215.
Kafarski, P.; Lejczak, B. Aminophosphonic acids of potential medical importance. Curr. Med. Chem. Anticancer Agents, 2001, 1, 301-312.
Kraicheva, I.; Bogomilova, A.; Tsacheva, I.; Momekov, G.; Troev, K. Synthesis, NMR characterization and in vitro antitumor evaluation of new aminophosphonic acid diesters. Eur. J. Med. Chem., 2009, 44, 3363-3367.
Klimczak, A.A.; Kuropatwa, A.; Lewkowski, J.; Szemraj, J. Synthesis of new N-arylamino(2-furyl)methylphosphonic acid diesters, and in vitro evaluation of their cytotoxicity against esophageal cancer cells. Med. Chem. Res., 2013, 22, 852-860.
Klimczak, A.A.; Matusiak, A.; Lewkowski, J.; Bitner, J.; Szemraj, J.; Kontek, R. Dimethyl (2-Furyl)-N-(2-Methoxyphenyl)Amino- methylphosphonate induces apoptosis in esophageal squamous cancer cells. structure versus activity of its selected analogs. Phosphorus Sulfur Silicon Relat. Elem., 2015, 190, 1088-1099.
Cunningham, D.; Atkin, W.; Lenz, H.J.; Lynch, H.T.; Minsky, B.; Nordlinger, B.; Starling, N. Colorectal cancer. Lancet, 2010, 375, 1030-1047.
Elmore, S. Apoptosis: A review of programmed cell death. Toxicol. Pathol., 2007, 35, 495-516.
Herr, I.; Debatin, K.M. Cellular stress response and apoptosis in cancer therapy. Blood, 2001, 98, 2603-2614.
Kim, R.; Tanabe, K.; Uchida, Y.; Emi, M.; Inoue, H.; Toge, T. Current status of the molecular mechanisms of anticancer drug-induced apoptosis the contribution of molecular-level analysis to cancer chemotherapy. Cancer Chemother. Pharmacol., 2002, 50, 343-352.
Arkin, M. Protein-protein interactions and cancer: small molecules going in for the kill. Curr. Opin. Chem. Biol., 2005, 9, 317-324.
Lewkowski, J.; Rodriguez Moya, M.; Wrona-Piotrowicz, A.; Zakrzewski, J.; Kontek, R.; Gajek, G. Synthesis, fluorescent properties and the promising cytotoxicity of pyrene–derived aminophosphonates. Beilstein J. Org. Chem., 2016, 12, 1229-1235.
Mosmann, T. Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays. Immunol. J. Methods, 1983, 65, 55-63.
Baell, J.B.; Holloway, G.A. New Substructure Filters for Removal of Pan Assay Interference Compounds (PAINS) from screening libraries and for their exclusion in bioassays. J. Med. Chem., 2010, 53, 2719-2740.
Kontek, R.; Jakubczak, M.; Matławska-Wasowska, K. The antioxidants, vitamin A and E but not vitamin C and melatonin enhance the proapoptotic effects of irinotecan in cancer cells in vitro. Toxicol. In Vitro, 2014, 28, 282-291.
Tyka, R. Novel synthesis of α-aminophosphonic acids. Tetrahedron Lett., 1970, 11, 677-680.
Wynberg, H.; Smaardijk, A. Asymmetric catalysis in carbon-phosphorus bond formation. Tetrahedron Lett., 1983, 24, 5899-5900.
Kalinowska, U.; Matławska, K.; Checinska, L.; Domagała, M.; Kontek, R.; Osiecka, R.; Ochocki, J. Synthesis, spectroscopy and antiproliferative activity of cis- and trans-platinum(II) complexes with diethyl (pyridin-4-ylmethyl)phosphate. X-ray crystal structure of trans-Pt(II) complex. J. Inorg. Biochem., 2005, 99, 2024-2031.

Rights & PermissionsPrintExport Cite as

Article Details

Year: 2019
Page: [453 - 462]
Pages: 10
DOI: 10.2174/1871520619666181122115649
Price: $58

Article Metrics

PDF: 39