Login Register Cart 0
Generic placeholder image

Current Organic Synthesis

Editor-in-Chief

ISSN (Print): 1570-1794
ISSN (Online): 1875-6271

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

Synthesis and Biological Evaluation of Paclitaxel-aminoguanidine Conjugates for Suppressing Breast Cancer

Author(s): Yi Dai*, Yang Zhang, Lvfeng Zhang and Zurong Song

Volume 20, Issue 8, 2023

Published on: 10 May, 2023

Page: [890 - 896] Pages: 7

DOI: 10.2174/1570179420666230327090545

Price: $65

Abstract

Background: A combination of paclitaxel with antineoplastic agents or paclitaxel alone was used clinically for the treatment of metastatic breast cancer. However, paclitaxel has poor water solubility and limited effect on some metastatic breast cancers. Hence, novel paclitaxel derivatives are in demand. In addition, the inducible nitric oxide synthase inhibitor, and aminoguanidine has a synergistic antitumor effect with chemotherapeutics.

Objective: This study aims to design and synthesize the paclitaxel-aminoguanidine conjugates. Upon cellular internalization, the novel paclitaxel-aminoguanidine conjugates could release paclitaxel and aminoguanidine with the aid of esterase and weak acids in cancer cells.

Methods: Paclitaxel-aminoguanidine conjugates were synthesized using click chemistry. The biological activity of paclitaxel-aminoguanidine conjugates was evaluated by MTT assay, determination of nitric oxide, analysis of apoptosis and cell cycle, and wound healing assay.

Results: Here, a novel paclitaxel-aminoguanidine conjugate was synthesized using click chemistry. Compared with paclitaxel, the water solubility of paclitaxel-aminoguanidine conjugates increased obviously. Upon cellular internalization, the novel paclitaxel-aminoguanidine conjugates released paclitaxel and aminoguanidine to synergistically inhibit the proliferation and metastasis of breast cancer cells with the aid of esterase and weak acids in cancer cells. The results of the MTT assay showed that compared with paclitaxel or the mixture of paclitaxel and aminoguanidine, the cytotoxicity of compound 4 against 4T1 cells was enhanced. As for apoptosis induced by these compounds, the paclitaxel-aminoguanidine conjugates also had a stronger ability to induce apoptosis than paclitaxel or the mixture of paclitaxel and aminoguanidine. The results of the scratch test showed that the anti-metastatic effect of the conjugate was the strongest among these tested compounds.

Conclusion: These findings indicate that paclitaxel-aminoguanidine conjugate is a promising anticancer agent worthy of further study.

Keywords: Paclitaxel, aminoguanidine, conjugate, synthesis, anti-proliferation, anti-metastasis.

« Previous Next »
Graphical Abstract

[1]
Zhao, S.; Tang, Y.; Wang, R.; Najafi, M. Mechanisms of cancer cell death induction by paclitaxel: An updated review. Apoptosis, 2022, 27(9-10), 647-667.
[http://dx.doi.org/10.1007/s10495-022-01750-z] [PMID: 35849264]
[2]
Sharifi-Rad, J.; Quispe, C.; Patra, J.K.; Singh, Y.D.; Panda, M.K.; Das, G.; Adetunji, C.O.; Michael, O.S.; Sytar, O.; Polito, L. Živković J.; Cruz-Martins, N.; Klimek-Szczykutowicz, M.; Ekiert, H.; Choudhary, M.I.; Ayatollahi, S.A.; Tynybekov, B.; Kobarfard, F.; Muntean, A.C.; Grozea, I.; Daştan, S.D.; Butnariu, M.; Szopa, A.; Calina, D. Paclitaxel: application in modern oncology and nanomedicine-based cancer therapy. Oxid. Med. Cell. Longev., 2021, 2021, 1-24.
[http://dx.doi.org/10.1155/2021/3687700] [PMID: 34707776]
[3]
Khanam, R.; Ahmad, K.; Hejazi, I.I.; Siddique, I.A.; Kumar, V.; Bhat, A.R.; Azam, A.; Athar, F. Inhibitory growth evaluation and apoptosis induction in MCF-7 cancer cells by new 5-aryl-2-butylthio-1,3,4-oxadiazole derivatives. Cancer Chemother. Pharmacol., 2017, 80(5), 1027-1042.
[http://dx.doi.org/10.1007/s00280-017-3414-6] [PMID: 28815320]
[4]
Abu Samaan, T.M.; Samec, M.; Liskova, A.; Kubatka, P.; Büsselberg, D. Paclitaxel’s mechanistic and clinical effects on breast cancer. Biomolecules, 2019, 9(12), 789.
[http://dx.doi.org/10.3390/biom9120789] [PMID: 31783552]
[5]
Yu, K.D.; Ye, F.G.; He, M.; Fan, L.; Ma, D.; Mo, M.; Wu, J.; Liu, G.Y.; Di, G.H.; Zeng, X.H.; He, P.Q.; Wu, K.J.; Hou, Y.F.; Wang, J.; Wang, C.; Zhuang, Z.G.; Song, C.G.; Lin, X.Y.; Toss, A.; Ricci, F.; Shen, Z.Z.; Shao, Z.M. Effect of adjuvant paclitaxel and carboplatin on survival in women with triple-negative breast cancer. JAMA Oncol., 2020, 6(9), 1390-1396.
[http://dx.doi.org/10.1001/jamaoncol.2020.2965] [PMID: 32789480]
[6]
Shi, X.; Yang, X.; Liu, M.; Wang, R.; Qiu, N.; Liu, Y.; Yang, H.; Ji, J.; Zhai, G. Chondroitin sulfate-based nanoparticles for enhanced chemo-photodynamic therapy overcoming multidrug resistance and lung metastasis of breast cancer. Carbohydr. Polym., 2021, 254117459
[http://dx.doi.org/10.1016/j.carbpol.2020.117459] [PMID: 33357918]
[7]
Jun, Y.J.; Min, J.H.; Ji, D.E.; Yoo, J.H.; Kim, J.H.; Lee, H.J.; Jeong, B.; Sohn, Y.S. A micellar prodrug of paclitaxel conjugated to cyclotriphosphazene. Bioorg. Med. Chem. Lett., 2008, 18(24), 6410-6413.
[http://dx.doi.org/10.1016/j.bmcl.2008.10.077] [PMID: 18990574]
[8]
Chen, T.; Chen, H.; Jiang, Y.; Yan, Q.; Zheng, S.; Wu, M. Co-delivery of 5-fluorouracil and paclitaxel in mitochondria-targeted kla-modified liposomes to improve triple-negative breast cancer treatment. Pharmaceuticals, 2022, 15(7), 881.
[http://dx.doi.org/10.3390/ph15070881] [PMID: 35890181]
[9]
Li, B.; Tan, T.; Chu, W.; Zhang, Y.; Ye, Y.; Wang, S.; Qin, Y.; Tang, J.; Cao, X. Co-delivery of paclitaxel (PTX) and docosahexaenoic acid (DHA) by targeting lipid nanoemulsions for cancer therapy. Drug Deliv., 2022, 29(1), 75-88.
[http://dx.doi.org/10.1080/10717544.2021.2018523] [PMID: 34964421]
[10]
Volk-Draper, L.; Hall, K.; Griggs, C.; Rajput, S.; Kohio, P.; DeNardo, D.; Ran, S. Paclitaxel therapy promotes breast cancer metastasis in a TLR4-dependent manner. Cancer Res., 2014, 74(19), 5421-5434.
[http://dx.doi.org/10.1158/0008-5472.CAN-14-0067] [PMID: 25274031]
[11]
Keklikoglou, I.; Cianciaruso, C.; Güç, E.; Squadrito, M.L.; Spring, L.M.; Tazzyman, S.; Lambein, L.; Poissonnier, A.; Ferraro, G.B.; Baer, C.; Cassará, A.; Guichard, A.; Iruela-Arispe, M.L.; Lewis, C.E.; Coussens, L.M.; Bardia, A.; Jain, R.K.; Pollard, J.W.; De Palma, M. Chemotherapy elicits pro-metastatic extracellular vesicles in breast cancer models. Nat. Cell Biol., 2019, 21(2), 190-202.
[http://dx.doi.org/10.1038/s41556-018-0256-3] [PMID: 30598531]
[12]
Hamada, H.; Ishihara, K.; Masuoka, N.; Mikuni, K.; Nakajima, N. Enhancement of water-solubility and bioactivity of paclitaxel using modified cyclodextrins. J. Biosci. Bioeng., 2006, 102(4), 369-371.
[http://dx.doi.org/10.1263/jbb.102.369] [PMID: 17116587]
[13]
Fukumura, D.; Kashiwagi, S.; Jain, R.K. The role of nitric oxide in tumour progression. Nat. Rev. Cancer, 2006, 6(7), 521-534.
[http://dx.doi.org/10.1038/nrc1910] [PMID: 16794635]
[14]
Cheng, H.; Wang, L.; Mollica, M.; Re, A.T.; Wu, S.; Zuo, L. Nitric oxide in cancer metastasis. Cancer Lett., 2014, 353(1), 1-7.
[http://dx.doi.org/10.1016/j.canlet.2014.07.014] [PMID: 25079686]
[15]
Wang, H.; Wang, L.; Xie, Z.; Zhou, S.; Li, Y.; Zhou, Y.; Sun, M. Nitric oxide (NO) and NO synthases (NOS)-based targeted therapy for colon cancer. Cancers, 2020, 12(7), 1881.
[http://dx.doi.org/10.3390/cancers12071881] [PMID: 32668616]
[16]
Garrido, P.; Shalaby, A.; Walsh, E.M.; Keane, N.; Webber, M.; Keane, M.M.; Sullivan, F.J.; Kerin, M.J.; Callagy, G.; Ryan, A.E.; Glynn, S.A. Impact of inducible nitric oxide synthase (iNOS) expression on triple negative breast cancer outcome and activation of EGFR and ERK signaling pathways. Oncotarget, 2017, 8(46), 80568-80588.
[http://dx.doi.org/10.18632/oncotarget.19631] [PMID: 29113326]
[17]
Flaherty, R.L.; Intabli, H.; Falcinelli, M.; Bucca, G.; Hesketh, A.; Patel, B.A.; Allen, M.C.; Smith, C.P.; Flint, M.S. Stress hormone-mediated acceleration of breast cancer metastasis is halted by inhibition of nitric oxide synthase. Cancer Lett., 2019, 459, 59-71.
[http://dx.doi.org/10.1016/j.canlet.2019.05.027] [PMID: 31132432]
[18]
Meng, Z.; Lv, Q.; Lu, J.; Yao, H.; Lv, X.; Jiang, F.; Lu, A.; Zhang, G. Prodrug strategies for paclitaxel. Int. J. Mol. Sci., 2016, 17(5), 796.
[http://dx.doi.org/10.3390/ijms17050796] [PMID: 27223283]
[19]
Martins, P.; Jesus, J.; Santos, S.; Raposo, L.; Roma-Rodrigues, C.; Baptista, P.; Fernandes, A. 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]
[20]
Lakshmithendral, K.; Saravanan, K.; Elancheran, R.; Archana, K.; Manikandan, N.; Arjun, H.A.; Ramanathan, M.; Lokanath, N.K.; Kabilan, S. Design, synthesis and biological evaluation of 2-(phenoxymethyl)-5-phenyl-1,3,4-oxadiazole derivatives as anti-breast cancer agents. Eur. J. Med. Chem., 2019, 168, 1-10.
[http://dx.doi.org/10.1016/j.ejmech.2019.02.033] [PMID: 30798049]
[21]
Zou, L.; Braegelman, A.S.; Webber, M.J. Dynamic supramolecular hydrogels spanning an unprecedented range of host–guest affinity. ACS Appl. Mater. Interfaces, 2019, 11(6), 5695-5700.
[http://dx.doi.org/10.1021/acsami.8b22151] [PMID: 30707553]
[22]
Doğan, H.; Doğan, Ş.D.; Gündüz, M.G.; Krishna, V.S.; Lherbet, C.; Sriram, D.; Şahin, O.; Sarıpınar, E. Discovery of hydrazone containing thiadiazoles as Mycobacterium tuberculosis growth and enoyl acyl carrier protein reductase (InhA) inhibitors. Eur. J. Med. Chem., 2020, 188112035
[http://dx.doi.org/10.1016/j.ejmech.2020.112035] [PMID: 31951850]
[23]
Song, Z.; Lu, Q.; Tao, A.; Wu, T. Synthesis and anti-cancer activity of paclitaxel-coumarin conjugate. Curr. Org. Synth., 2021, 18(6), 587-591.
[http://dx.doi.org/10.2174/1570179418666210303113406] [PMID: 33655867]
[24]
Elancheran, R.; Saravanan, K.; Choudhury, B.; Divakar, S.; Kabilan, S.; Ramanathan, M.; Das, B.; Devi, R.; Kotoky, J. Design and development of oxobenzimidazoles as novel androgen receptor antagonists. Med. Chem. Res., 2016, 25(4), 539-552.
[http://dx.doi.org/10.1007/s00044-016-1504-3]

Rights & Permissions Print Cite
Article Metrics
41
3
© 2024 Bentham Science Publishers | Privacy Policy