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Letters in Drug Design & Discovery

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ISSN (Print): 1570-1808
ISSN (Online): 1875-628X

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Research Article

Design, Synthesis, Biological Evaluation and Molecular Docking Studies of 5-fluorouracil-dithiocarbamate Conjugates

Author(s): Yifeng Zhan, Youyun Wang, Shibo He, Hongda Zhu, Huiling Guo, Hongmei Sun and Mingxing Liu*

Volume 21, Issue 6, 2024

Published on: 27 February, 2023

Page: [1120 - 1136] Pages: 17

DOI: 10.2174/1570180820666230203113746

Price: $65

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Abstract

Background: Novel anti-tumor bioactivity compounds were designed by the strategy of modular hybridization with the bioactivity advantages of 5-fluorouracil and dithiocarbamate derivatives.

Methods: A series of novel 5-fluorouracil-dithiocarbamate conjugates were synthesized, characterized and evaluated for their cytotoxic activities in vitro against B16, Hela and U87MG by MTT assay. Colonyformation, transwell migration, cell apoptosis and cell cycle distribution assays were performed to explore the anti-tumor activities and mechanism of conjugates for compounds P3 and P4. Conjugates, dithiocarbamate derivatives combined with copper ions and 5-fluorouracil were investigated by molecular docking.

Results: The results of cytotoxicity assays illuminated that these conjugates had anti-tumor activity against B16, Hela and U87MG. Interestingly, the cytotoxicity of these conjugates was significantly increased when combined with copper ions, and compound P3 displayed better bioactivity compared to the other compounds. Conjugates might be metabolized in the cells to produce dithiocarbamates, and then metabolites formed complexes with copper ions, generating better anti-tumor effects. Molecular docking studies exhibited that compound P3 appeared the strongest interaction with the receptors 6CCY and 5T92.

Conclusion: Compound P3 exhibited better anti-tumor bioactivity and might be emerged as the lead compound for the treatment of glioma. Further research in vivo will be performed in our following work.

Keywords: 5-fluorouracil, dithiocarbamate derivatives, modular hybridization, synthesis, biological evaluation, molecular docking, U87MG, MTT assay.

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[1]
Garcia, M.; Jemal, A.; Ward, E.M.; Center, M.M.; Thun, M.J. Global cancer facts & figures 2007; American cancer society, 2007, pp. 1-44.
[2]
Stratton, M.R.; Campbell, P.J.; Futreal, P.A. The cancer genome. Nature, 2009, 458(7239), 719-724.
[http://dx.doi.org/10.1038/nature07943] [PMID: 19360079]
[3]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[4]
Gibbs, J.B. Mechanism-based target identification and drug discovery in cancer research. Science, 2000, 287(5460), 1969-1973.
[http://dx.doi.org/10.1126/science.287.5460.1969] [PMID: 10720316]
[5]
Portt, L.; Norman, G.; Clapp, C.; Greenwood, M.; Greenwood, M.T. Anti-apoptosis and cell survival: A review. Biochim. Biophys. Acta Mol. Cell Res., 2011, 1813(1), 238-259.
[http://dx.doi.org/10.1016/j.bbamcr.2010.10.010] [PMID: 20969895]
[6]
Andón, F.T.; Fadeel, B. Programmed cell death: molecular mechanisms and implications for safety assessment of nanomaterials. Acc. Chem. Res., 2013, 46(3), 733-742.
[http://dx.doi.org/10.1021/ar300020b] [PMID: 22720979]
[7]
Lagoja, I.M. Pyrimidine as constituent of natural biologically active compounds. Chem. Biodivers., 2005, 2(1), 1-50.
[http://dx.doi.org/10.1002/cbdv.200490173] [PMID: 17191918]
[8]
Hou, Y.; Zhu, L.; Li, Z.; Shen, Q.; Xu, Q.; Li, W.; Liu, Y.; Gong, P. Design, synthesis and biological evaluation of novel 7-amino-[1,2,4]triazolo[4,3-f]pteridinone, and 7-aminotetrazolo[1,5-f]pteridi-none derivative as potent antitumor agents. Eur. J. Med. Chem., 2019, 163, 690-709.
[http://dx.doi.org/10.1016/j.ejmech.2018.12.009] [PMID: 30572179]
[9]
Longley, D.B.; Harkin, D.P.; Johnston, P.G. 5-Fluorouracil: mechanisms of action and clinical strategies. Nat. Rev. Cancer, 2003, 3(5), 330-338.
[http://dx.doi.org/10.1038/nrc1074] [PMID: 12724731]
[10]
Houghton, J.A. Death receptor signaling in the mechanism of 5-fluorouracil action. In: Fluoropyrimidines in Cancer Therapy. Cancer Drug Discovery and Development; Rustum, Y.M., Ed.; Human Press: Totowa, NJ, 2003; pp. 93-105.
[11]
Ma, L.Y.; Wang, B.; Pang, L.P.; Zhang, M.; Wang, S.Q.; Zheng, Y.C.; Shao, K.P.; Xue, D.Q.; Liu, H.M. Design and synthesis of novel 1,2,3-triazole–pyrimidine–urea hybrids as potential anticancer agents. Bioorg. Med. Chem. Lett., 2015, 25(5), 1124-1128.
[http://dx.doi.org/10.1016/j.bmcl.2014.12.087] [PMID: 25655718]
[12]
Duan, Y.C.; Zheng, Y.C.; Li, X.C.; Wang, M.M.; Ye, X.W.; Guan, Y.Y.; Liu, G.Z.; Zheng, J.X.; Liu, H.M. Design, synthesis and antiproliferative activity studies of novel 1,2,3-triazole–dithiocarbamate–urea hybrids. Eur. J. Med. Chem., 2013, 64, 99-110.
[http://dx.doi.org/10.1016/j.ejmech.2013.03.058] [PMID: 23644193]
[13]
Orrenius, S.; Nobel, C.S.I.; van den Dobbelsteen, D.J.; Burkitt, M.J.; Slater, A.F.G. Dithiocarbamates and the redox regulation of cell death. Biochem. Soc. Trans., 1996, 24(4), 1032-1038.
[http://dx.doi.org/10.1042/bst0241032] [PMID: 8968507]
[14]
Somers, P.K.; Medford, R.M.; Saxena, U. Dithiocarbamates: effects on lipid hydroperoxides and vascular inflammatory gene expression. Free Radic. Biol. Med., 2000, 28(10), 1532-1537.
[http://dx.doi.org/10.1016/S0891-5849(00)00257-4] [PMID: 10927178]
[15]
Johansson, B. A review of the pharmacokinetics and pharmacodynamics of disulfiram and its metabolites. Acta Psychiatr. Scand., 1992, 86(S369), 15-26.
[http://dx.doi.org/10.1111/j.1600-0447.1992.tb03310.x] [PMID: 1471547]
[16]
Yu, S.; Wang, N.; Chai, X.; Wang, B.; Cui, H.; Zhao, Q.; Zou, Y.; Sun, Q.; Meng, Q.; Wu, Q. Synthesis and antifungal activity of the novel triazole derivatives containing 1,2,3-triazole fragment. Arch. Pharm. Res., 2013, 36(10), 1215-1222.
[http://dx.doi.org/10.1007/s12272-013-0063-0] [PMID: 23640383]
[17]
Kang, M.S.; Choi, E.K.; Choi, D.H.; Ryu, S.Y.; Lee, H.H.; Kang, H.C.; Koh, J.T.; Kim, O.S.; Hwang, Y.C.; Yoon, S.J.; Kim, S.M.; Yang, K.H.; Kang, I.C. Antibacterial activity of pyrrolidine dithiocarbamate. FEMS Microbiol. Lett., 2008, 280(2), 250-254.
[http://dx.doi.org/10.1111/j.1574-6968.2008.01069.x] [PMID: 18248425]
[18]
Carta, F.; Aggarwal, M.; Maresca, A.; Scozzafava, A.; McKenna, R.; Masini, E.; Supuran, C.T. Dithiocarbamates strongly inhibit carbonic anhydrases and show antiglaucoma action in vivo. J. Med. Chem., 2012, 55(4), 1721-1730.
[http://dx.doi.org/10.1021/jm300031j] [PMID: 22276570]
[19]
Cheriyan, V.T.; Wang, Y.; Muthu, M.; Jamal, S.; Chen, D.; Yang, H.; Polin, L.A.; Tarca, A.L.; Pass, H.I.; Dou, Q.P.; Sharma, S.; Wali, A.; Rishi, A.K. Disulfiram suppresses growth of the malignant pleural mesothelioma cells in part by inducing apoptosis. PLoS One, 2014, 9(4), e93711.
[http://dx.doi.org/10.1371/journal.pone.0093711] [PMID: 24690739]
[20]
Zha, J.; Chen, F.; Dong, H.; Shi, P.; Yao, Y.; Zhang, Y.; Li, R.; Wang, S.; Li, P.; Wang, W.; Xu, B. Disulfiram targeting lymphoid malignant cell lines via ROS-JNK activation as well as Nrf2 and NF-kB pathway inhibition. J. Transl. Med., 2014, 12(1), 163.
[http://dx.doi.org/10.1186/1479-5876-12-163] [PMID: 24915933]
[21]
Chen, D.; Cui, Q.C.; Yang, H.; Dou, Q.P. Disulfiram, a clinically used anti-alcoholism drug and copper-binding agent, induces apoptotic cell death in breast cancer cultures and xenografts via inhibition of the proteasome activity. Cancer Res., 2006, 66(21), 10425-10433.
[http://dx.doi.org/10.1158/0008-5472.CAN-06-2126] [PMID: 17079463]
[22]
Allensworth, J.L.; Evans, M.K.; Bertucci, F.; Aldrich, A.J.; Festa, R.A.; Finetti, P.; Ueno, N.T.; Safi, R.; McDonnell, D.P.; Thiele, D.J.; Van Laere, S.; Devi, G.R. Disulfiram (DSF) acts as a copper ionophore to induce copper-dependent oxidative stress and mediate anti-tumor efficacy in inflammatory breast cancer. Mol. Oncol., 2015, 9(6), 1155-1168.
[http://dx.doi.org/10.1016/j.molonc.2015.02.007] [PMID: 25769405]
[23]
Valeriote, F.; Grates, H.E. Potentiation of nitrogen mustard cytotoxicity by disulfiram, diethyldithiocarbamic acid, and diethylamine in mice. Cancer Res., 1989, 49(23), 6658-6661.
[PMID: 2555050]
[24]
Wang, W.; McLeod, H.L.; Cassidy, J. Disulfiram-mediated inhibition of NF-?B activity enhances cytotoxicity of 5-fluorouracil in human colorectal cancer cell lines. Int. J. Cancer, 2003, 104(4), 504-511.
[http://dx.doi.org/10.1002/ijc.10972] [PMID: 12584750]
[25]
Gu, J.W.; Young, E.; Busby, B.; Covington, J.; Johnson, J.W. Oral administration of Pyrrolidine Dithiocarbamate (PDTC) inhibits VEGF expression, tumor angiogenesis, and growth of breast cancer in female mice. Cancer Biol. Ther., 2009, 8(6), 514-521.
[http://dx.doi.org/10.4161/cbt.8.6.7689] [PMID: 19242105]
[26]
Skrott, Z.; Mistrik, M.; Andersen, K.K.; Friis, S.; Majera, D.; Gursky, J.; Ozdian, T.; Bartkova, J.; Turi, Z.; Moudry, P.; Kraus, M.; Michalova, M.; Vaclavkova, J.; Dzubak, P.; Vrobel, I.; Pouckova, P.; Sedlacek, J.; Miklovicova, A.; Kutt, A.; Li, J.; Mattova, J.; Driessen, C.; Dou, Q.P.; Olsen, J.; Hajduch, M.; Cvek, B.; Deshaies, R.J.; Bartek, J. Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4. Nature, 2017, 552(7684), 194-199.
[http://dx.doi.org/10.1038/nature25016] [PMID: 29211715]
[27]
Ahmad, S.B.; McNeill, F.E.; Byun, S.H.; Prestwich, W.V.; Mothersill, C.; Seymour, C.; Armstrong, A.; Fernandez, C. Ultra-violet light emission from hpv-g cells irradiated with low let radiation from 90y; consequences for radiation induced bystander effects. Dose Response, 2013, 11(4), 498-516.
[http://dx.doi.org/10.2203/dose-response.12-048.Ahmad] [PMID: 24298227]
[28]
Nagorsen, D.; Rüttinger, D. Immunotherapy of colorectal cancer. Memo-Mag. Eur. Med. Onc., 2008, 1(4), 205-210.
[29]
Weber, D.D.; Aminzadeh-Gohari, S.; Tulipan, J.; Catalano, L.; Feichtinger, R.G.; Kofler, B. Ketogenic diet in the treatment of cancer – Where do we stand? Mol. Metab., 2020, 33, 102-121.
[http://dx.doi.org/10.1016/j.molmet.2019.06.026] [PMID: 31399389]
[30]
Al-Lazikani, B.; Banerji, U.; Workman, P. Combinatorial drug therapy for cancer in the post-genomic era. Nat. Biotechnol., 2012, 30(7), 679-692.
[http://dx.doi.org/10.1038/nbt.2284] [PMID: 22781697]
[31]
Miles, D.; Minckwitz, G.; Seidman, A.D. Combination versus sequential single-agent therapy in metastatic breast cancer. Oncologist, 2002, 7(S6)(Suppl. 6), 13-19.
[http://dx.doi.org/10.1634/theoncologist.2002-0013] [PMID: 12454315]
[32]
Beh, C.Y.; How, C.W.; Foo, J.B.; Foong, J.N.; Selvarajah, G.T.; Rasedee, A. Development of erythropoietin receptor-targeted drug delivery system against breast cancer using tamoxifen-loaded nanostructured lipid carriers. Drug Des. Devel. Ther., 2017, 11, 771-782.
[http://dx.doi.org/10.2147/DDDT.S123939] [PMID: 28352153]
[33]
Witt-Enderby, P.A.; Davis, V.L.; Lapinsky, D. Anti-cancer tamoxifen- melatonin hybrid ligand US, Patent 8, 785, 501, July 22, 2014.
[34]
Zhang, Q.; Xu, Y.; Lv, J.; Cheng, M.; Wu, Y.; Cao, K.; Zhang, X.; Mou, X.; Fan, Q. New utilization of Polygonum multiflorum polysaccharide as macromolecular carrier of 5-fluorouracil for controlled release and immunoprotection. Int. J. Biol. Macromol., 2018, 116, 1310-1316.
[http://dx.doi.org/10.1016/j.ijbiomac.2018.02.052] [PMID: 29432832]
[35]
Schwartz, G.K.; Shah, M.A. Targeting the cell cycle: a new approach to cancer therapy. J. Clin. Oncol., 2005, 23(36), 9408-9421.
[http://dx.doi.org/10.1200/JCO.2005.01.5594] [PMID: 16361640]
[36]
Meier, S.; Cantilena, S.; Niklison Chirou, M.V.; Anderson, J.; Hargrave, D.; Salomoni, P.; de Boer, J.; Michod, D. Alcohol-abuse drug disulfiram targets pediatric glioma via MLL degradation. Cell Death Dis., 2021, 12(8), 785.
[http://dx.doi.org/10.1038/s41419-021-04078-9] [PMID: 34381018]
[37]
Romena, G.; Nguyen, L.; Berg, K.; Madsen, S.J.; Hirschberg, H. Enhanced gene transfection of macrophages by photochemical internalization: Potential for gene-directed enzyme prodrug therapy of gliomas. Photodiagn. Photodyn. Ther., 2021, 33, 102098.
[http://dx.doi.org/10.1016/j.pdpdt.2020.102098] [PMID: 33188941]
[38]
Abu-Serie, M.M.; Eltarahony, M. Novel nanoformulation of disulfiram with bacterially synthesized copper oxide nanoparticles for augmenting anticancer activity: an in vitro study. Cancer Nanotechnol., 2021, 12(1), 25.
[http://dx.doi.org/10.1186/s12645-021-00097-5] [PMID: 33456622]
[39]
Pooresmaeil, M.; Asl, E.A.; Namazi, H. A new pH-sensitive CS/Zn-MOF@GO ternary hybrid compound as a biofriendly and implantable platform for prolonged 5-Fluorouracil delivery to human breast cancer cells. J. Alloys Compd., 2021, 885, 160992.
[http://dx.doi.org/10.1016/j.jallcom.2021.160992]

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