Login Register Cart 0
Generic placeholder image

Medicinal Chemistry

Editor-in-Chief

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

Back
Journal Home About Journal Editorial Board Journal Insight Current Issue Volumes/Issues
Subscribe
Research Article

Improvement of the Anticancer Activity of Chlorambucil and Ibuprofen via Calix[4]arene Conjugates

Author(s): Luis D. Pedro-Hernández, Ulises Organista-Mateos, Luis I. Allende-Alarcón, Elena Martínez-Klimova*, Teresa Ramírez-Ápan and Marcos Martínez-García

Volume 16, Issue 7, 2020

Page: [984 - 990] Pages: 7

DOI: 10.2174/1573406415666190826162339

Price: $65

Abstract

Background: One of the possible ways of improving the activity and selectivity profile of anticancer agents is to design drug carrier systems employing nanomolecules. Calix[4]arene derivatives and chlorambucil and ibuprofen are important compounds that exhibit interesting anticancer properties.

Objective: The objective of this article is the synthesis of new calix[4]arene-derivative conjugates of chlorambucil or ibuprofen with potential anticancer activity.

Methods: Cytotoxicity assays were determined using the protein-binding dye sulforhodamine B (SRB) in microculture to measure cell growth as described [19, 20]. Conjugates of chlorambucil and resorcinarene-dendrimers were prepared in 2% DMSO and added into the culture medium immediately before use. Control cells were treated with 2% DMSO.

Results: Thus, calix[4]arene-derivative conjugates of chlorambucil or ibuprofen showed good stability of the chemical link between drug and spacer. Evaluation of the cytotoxicity of the calix[4]arene chlorambucil or ibuprofen conjugates employing a sulforhodamine B (SRB) assay in K-562 (human chronic myelogenous leukemia cells) and U-251 (human glioblastoma cells) demonstrated that the conjugate was more potent as an antiproliferative agent than free chlorambucil and ibuprofen. The conjugates did not show any activity against the COS-7 African green monkey kidney fibroblast cell line.

Conclusion: In the paper, we report the synthesis and spectroscopic analyses of new calix[4]arene derivative conjugates of chlorambucil or ibuprofen. Cytotoxicity assays revealed that at 10 μM, the conjugates were very active against K-562 (human chronic myelogenous leukemia cells) and U- 251 (human glioblastoma cells) cancer cells' proliferation. In order to explain the molecular mechanisms involved in the anticancer activity of calix[4]arene chlorambucil or ibuprofen conjugates, our research will be continued.

Keywords: Chlorambucil, calixarenes, ibuprofen, calix[4]arene derivatives, anticancer activity, human glioblastoma cells.

« Previous Next »
Graphical Abstract

[1]
Gutsche, D. Calixarenes: an introduction. (The royal Society of Chemistry, Cambridge 2008.
[2]
Vicens, J.; Harrowfield, J. Calixarenes in the nanoworld; Springer: Dordrecht, Netherlands, 2006.
[3]
Arena, G.; Casnati, A.; Contino, A.; Mirone, L.; Sciotto, D.; Ungaro, R. Synthesis of new calixcrowns and their anchoring to silica gel for the selective separation of Cs+ and K+. Chem. Commun. (Camb.), 1996, 19, 2277-2278.
[http://dx.doi.org/10.1039/cc9960002277]
[4]
Guérineau, V.; Rollet, M.; Viel, S.; Lepoittevin, B.; Costa, L.; Saint-Aguet, P.; Laurent, R.; Roger, P.; Gigmes, D.; Martini, C.; Huc, V. The synthesis and characterization of giant Calixarenes. Nat. Commun., 2019, 10(1), 113-114.
[http://dx.doi.org/10.1038/s41467-018-07751-4] [PMID: 30631073]
[5]
Marradi, M.; Cicchi, S.; Sansone, F.; Casnati, A.; Goti, A. Low-generation dendrimers with a calixarene core and based on a chiral C(2)-symmetric pyrrolidine as iminosugar mimics. Beilstein J. Org. Chem., 2012, 8, 951-957.
[http://dx.doi.org/10.3762/bjoc.8.107] [PMID: 23015845]
[6]
Yan, C.G.; An, L.; Sun, J. Novel synthesis of p-tert-butylcalix[n]arenes bearing ethylene glycol ether chains. Synth. Commun., 2004, 34, 4493-4497.
[http://dx.doi.org/10.1081/SCC-200043196]
[7]
Yan, C.G.; An, L.; Wang, Y.; Sun, J. Novel synthesis of calix[n]arene amide supramolecular receptor. J. Chem. Res., 2004, 10, 710-711.
[http://dx.doi.org/10.3184/0308234043431915]
[8]
An, L.; Cai, Y.H.; Wang, M.H.; Yan, C.G. Novel synthesis of calix[n]arene amidoazobenzene derivatives. J. Chem. Res., 2006, 2, 75-77.
[http://dx.doi.org/10.3184/030823406776330909]
[9]
Rodik, R.V.; Boyko, V.I.; Kalchenko, V.I. Calixarenes in bio-medical researches., Curr. Med. Chem., 2009, 16(13), 1630-1655..
[http://dx.doi.org/0.2174/092986709788186219] [PMID: 19442137]
[10]
Yousaf, A.; Hamid, S.A.; Bunnori, N.M.; Ishola, A.A. Applications of calixarenes in cancer chemotherapy: facts and perspectives., Drug Des. Devel. Ther., 2015, 9, 2831-2838.
[PMID: 26082613]
[11]
Grazia, M.L.; Granata, G.; Galantea, E.; Di Silvestro, I.; Salafia, L.; Geraci, C. Synthesis of water-soluble nucleotide-calixarene conjugates and preliminary investigation of their in vitro DNA replication inhibitory activity. Tetrahedron, 2007, 63, 10758-10763.
[http://dx.doi.org/10.1016/j.tet.2007.06.123]
[12]
Soares, M.N.; Gascon, T.M.; Fonseca, F.L.A.; Ferreira, K.S.; Bagatin, I.A. Evaluation of the biological effects of 5-Cl-8- oxyquinolinepropoxycalix[4]arene and 8-oxyquinoline propoxy calix[4]arene in vitro and in vivo. Mater. Sci. Eng., 2014, C, 40-, 260-266..
[13]
Sun, J.; Wang, D.A.; Jain, R.K.; Carie, A.; Paquette, S.; Ennis, E.; Blaskovich, M.A.; Baldini, L.; Coppola, D.; Hamilton, A.D.; Sebti, S.M. Inhibiting angiogenesis and tumorigenesis by a synthetic molecule that blocks binding of both VEGF and PDGF to their receptors. Oncogene, 2005, 24(29), 4701-4709.
[http://dx.doi.org/10.1038/sj.onc.1208391] [PMID: 15897913]
[14]
Dings, R.P.M.; Chen, X.; Hellebrekers, D.M.; van Eijk, L.I.; Zhang, Y.; Hoye, T.R.; Griffioen, A.W.; Mayo, K.H. Design of nonpeptidic topomimetics of antiangiogenic proteins with antitumor activities. J. Natl. Cancer Inst., 2006, 98(13), 932-936.
[http://dx.doi.org/10.1093/jnci/djj247] [PMID: 16818857]
[15]
Dings, R.P.M.; Levine, J.I.; Brown, S.G.; Astorgues-Xerri, L.; MacDonald, J.R.; Hoye, T.R.; Raymond, E.; Mayo, K.H. Polycationic calixarene PTX013, a potent cytotoxic agent against tumors and drug resistant cancer. Invest. New Drugs, 2013, 31(5), 1142-1150.
[http://dx.doi.org/10.1007/s10637-013-9932-0] [PMID: 23392775]
[16]
Pelizzaro-Rocha, K.J.; de Jesus, M.B.; Ruela-de-Sousa, R.R.; Nakamura, C.V.; Reis, F.S.; de Fátima, A.; Ferreira-Halder, C.V. Calix[6]arene bypasses human pancreatic cancer aggressiveness: downregulation of receptor tyrosine kinases and induction of cell death by reticulum stress and autophagy. Biochim. Biophys. Acta, 2013, 1833(12), 2856-2865..
[http://dx.doi.org/0.1016/j.bbamcr.2013.07.010] [PMID: 23872419]
[17]
Zhao, Z.M.; Wang, Y.; Han, J.; Zhu, H.D.; An, L. Preparation and characterization of amphiphilic calixarene nanoparticles as delivery carriers for paclitaxel. Chem. Pharm. Bull. (Tokyo), 2015, 63(3), 180-186.
[http://dx.doi.org/10.1248/cpb.c14-00699] [PMID: 25757488]
[18]
Pedro-Hernández, L.D.; Martínez-Klimova, E.; Cortez-Maya, S.; Mendoza-Cardozo, S.; Ramírez-Ápan, T.; Martínez-García, M. Synthesis, characterization, and nanomedical applications of conjugates between resorcinarene-dendrimers and ibuprofen. Nanomaterials (Basel), 2017, 7(7), 163-173.
[http://dx.doi.org/10.3390/nano7070163] [PMID: 28665319]
[19]
Mendoza-Cardozo, S.; Pedro-Hernández, L.D.; Organista-Mateos, U.; Allende-Alarcón, L.I.; Martínez-Klimova, E.; Ramírez-Ápan, T.; Martínez-García, M. In vitro activity of resorcinarene-chlorambucil conjugates for therapy in human chronic myelogenous leukemia cells. Drug Dev. Ind. Pharm., 2019, 45(4), 683-688,
[http://dx.doi.org/10.1080/03639045.2019.1569036] [PMID: 0633576]
[20]
Monks, A.; Scudiero, D.; Skehan, P.; Shoemaker, R.; Paull, K.; Vistica, D.; Hose, C.; Langley, J.; Cronise, P.; Vaigro-Wolff, A. Feasibility of a high-flux anticancer drug screen using a diverse panel of cultured human tumor cell lines. J. Natl. Cancer Inst., 1991, 83(11), 757-766.
[http://dx.doi.org/10.1093/jnci/83.11.757] [PMID: 2041050]
[21]
An, L.; Han, L.L.; Zheng, Y.G.; Peng, X.N.; Xue, Y.S.; Gu, X.K.; Sun, J.; Yan, C.G. Synthesis, X-ray crystal structure and anti-tumor activity of calix[n]arene polyhydroxyamine derivatives. Eur. J. Med. Chem., 2016, 123, 21-30.
[http://dx.doi.org/10.1016/j.ejmech.2016.07.016] [PMID: 27474920]
[22]
Neises, B.; Steglich, W. Simple method for the esterification of carboxylic acids. Angew. Chem. Int. Ed. Engl., 1978, 17(7), 522-524.
[http://dx.doi.org/10.1002/anie.197805221]

Rights & Permissions Print Cite
Article Metrics
27
© 2024 Bentham Science Publishers | Privacy Policy