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Abstract

Introduction

The decreased anticancer activity of paclitaxel was associated with many factors. The inactivity of p53 was one of the important causes. Some chalcones and their derivatives were found to inhibit the MDM2-p53 interaction. Therefore, the conjugation of chalcones with paclitaxel might be an effective strategy for enhancing the antitumor activity of paclitaxel.

Methods

Here, three novel chalones, compounds , and were first designed and synthesized, followed by the conjugation of them with paclitaxel to prepare compounds , and . The anti-tumor activity of the aforementioned three novel paclitaxel-chalcone conjugates was evaluated by the MTT method, mitochondrial membrane potential analysis, apoptosis assay, and molecular docking.

Results

The MTT assay demonstrated that compound exhibited superior cytotoxicity compared to and toward breast cancer MCF-7 cells and MDA-MB-231 cells, with the differential activity correlating with electronic effects of their chalcone substituents: compound possessed two electron-withdrawing chlorine groups, compound lacked substitution, and compound featured an electron-donating morpholine. Compared to paclitaxel, compound 2a exhibited a 1.7-fold enhancement in cytotoxic activity against MCF-7 cells and a 2.5-fold increase in potency against MDA-MB-231 cells. Further investigation showed that compound could effectively decrease the mitochondrial membrane potential and induce cell apoptosis. Computational docking studies showed compound formed two hydrogen bonds and one π-H interaction with MDM2, with a docking score of -8.5317.

Discussion

Research findings demonstrate that the designed chalcone derivatives can effectively inhibit MDM2 activity, with the inhibitory potency closely associated with the substituents on the chalcone core. Notably, the introduction of chlorine substituents not only enhances the binding affinity to MDM2 but also improves the antitumor activity of its hybrid with paclitaxel. Molecular docking analysis reveals that the chlorine-substituted chalcone forms a π-H interaction with Gln72 of MDM2, a feature absent in the other two designed chalcone structures. Furthermore, the chlorine substituent may increase the lipophilicity of the hybrid, facilitating cellular uptake and thereby potentiating its anticancer efficacy.

Conclusion

These findings indicated that the conjugation of paclitaxel with chalones might be an effective strategy for strengthening the anticancer activity of paclitaxel.

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2025-08-12
2025-09-14

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References

  1. 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 10.3390/biom9120789 31783552
    [Google Scholar]
  2. Weaver B.A. How Taxol/paclitaxel kills cancer cells. Mol. Biol. Cell 2014 25 18 2677 2681 10.1091/mbc.e14‑04‑0916 25213191
    [Google Scholar]
  3. Hayashi A. Kamio K. Miyanaga A. Yoshida K. Noro R. Matsuda K. Tozuka T. Omori M. Hirao M. Fukuizumi A. Hisakane K. Takeuchi S. Matsumoto M. Kasahara K. Amano T. Honda K. Seike M. Ivermectin enhances paclitaxel efficacy by overcoming resistance through modulation of ABCB1 in non-small cell lung cancer. Anticancer Res. 2024 44 12 5271 5282 10.21873/anticanres.17355 39626921
    [Google Scholar]
  4. Deng S. Li W. Chen Q. Shao J. Zhang J. Wang Y. Li Y. Developing a novel p-glycoprotein inhibitor and pairing it with oral paclitaxel liposomes for enhanced cancer therapy. Biomed. Pharmacother. 2024 180 117577 [Nov
    [Google Scholar]
  5. Said A.M. Mansour Y.E. Soliman R.R. Islam R. Fatahala S.S. Design, synthesis, molecular modeling, in vitro and in vivo biological evaluation of potent anthranilamide derivatives as dual P-glycoprotein and CYP3A4 inhibitors. Eur. J. Med. Chem. 2024 273 116492 10.1016/j.ejmech.2024.116492 38762918
    [Google Scholar]
  6. Wang Y. Pei W. Yang Y. Xia C. Zhang Q. Geng Z. Shi X. Wang F. Inhibition of XIST restrains paclitaxel resistance in breast cancer cells by targeting hsa-let-7d-5p/ATG16L1 through regulation of autophagy. Cell. Signal. 2025 127 111534 10.1016/j.cellsig.2024.111534 39638138
    [Google Scholar]
  7. Yang B. Li G. Wang S. Zheng Y. Zhang J. Pan B. Wang N. Wang Z. Tumor-associated macrophages/C-X-C motif chemokine ligand 1 promotes breast cancer autophagy-mediated chemoresistance via IGF1R/STAT3/HMGB1 signaling. Cell Death Dis. 2024 15 10 743 10.1038/s41419‑024‑07123‑5 39394189
    [Google Scholar]
  8. Zheng B. Qian F. Wang X. Wang Y. Zhou B. Fang L. Neddylation activated TRIM25 desensitizes triple-negative breast cancer to paclitaxel via TFEB-mediated autophagy. J. Exp. Clin. Cancer Res. 2024 43 1 177 10.1186/s13046‑024‑03085‑w 38926803
    [Google Scholar]
  9. Xu H. Du Z. Li Z. Liu X. Li X. Zhang X. Ma J. MUC1-EGFR crosstalk with IL-6 by activating NF-κB and MAPK pathways to regulate the stemness and paclitaxel-resistance of lung adenocarcinoma. Ann. Med. 2024 56 1 2313671 10.1080/07853890.2024.2313671 38325364
    [Google Scholar]
  10. Tsurushima K. Tsubaki M. Takeda T. Matsuda T. Kimura A. Takefuji H. Okada A. Sakamoto C. Ishizaka T. Nishida S. Dimethyl fumarate induces apoptosis via inhibition of NF-κB and enhances the effect of paclitaxel and adriamycin in human TNBC cells. Int. J. Mol. Sci. 2022 23 15 8681 10.3390/ijms23158681 35955813
    [Google Scholar]
  11. Qi M. Yi X. Yue B. Huang M. Zhou S. Xiong J. S100A6 inhibits MDM2 to suppress breast cancer growth and enhance sensitivity to chemotherapy. Breast Cancer Res. 2023 25 1 55 10.1186/s13058‑023‑01657‑w 37217945
    [Google Scholar]
  12. Shen H. Dong W. Gao D. Wang G. Ma G. Liu Q. Du J. MDM2 antagonist Nutlin-3a protects wild-type p53 cancer cells from paclitaxel. Chin. Sci. Bull. 2012 57 9 1007 1012 10.1007/s11434‑012‑4984‑7
    [Google Scholar]
  13. Wei C. Du J. Shen Y. Wang Z. Lin Q. Chen J. Zhang F. Lin W. Wang Z. Yang Z. Ma W. Anticancer effect of involucrasin A on colorectal cancer cells by modulating the Akt/MDM2/p53 pathway. Oncol. Lett. 2023 25 6 218 10.3892/ol.2023.13804 37153032
    [Google Scholar]
  14. Han N.R. Kim H.Y. Kang S. Kim M.H. Yoon K.W. Moon P.D. Kim H.M. Jeong H.J. Chrysophanol, an anthraquinone from AST2017-01, possesses the anti-proliferative effect through increasing p53 protein levels in human mast cells. Inflamm. Res. 2019 68 7 569 579 10.1007/s00011‑019‑01239‑7 31055607
    [Google Scholar]
  15. Bhatia N. Khator R. Kulkarni S. Singh Y. Kumar P. Thareja S. Recent advancements in the discovery of MDM2/MDM2-p53 interaction inhibitors for the treatment of cancer. Curr. Med. Chem. 2023 30 32 3668 3701 10.2174/0929867330666221114103924 37190755
    [Google Scholar]
  16. Muhseen Z.T. Li G. Promising terpenes as natural antagonists of cancer: An in-silico approach. Molecules 2019 25 1 155 10.3390/molecules25010155 31906032
    [Google Scholar]
  17. Moreira J. Almeida J. Saraiva L. Cidade H. Pinto M. Chalcones as promising antitumor agents by targeting the p53 pathway: An overview and new insights in drug-likeness. Molecules 2021 26 12 3737 10.3390/molecules26123737 34205272
    [Google Scholar]
  18. Chakrabarti K. Paul B. Maji M. Roy B.C. Shee S. Kundu S. Bifunctional Ru(ii) complex catalysed carbon–carbon bond formation: An eco-friendly hydrogen borrowing strategy. Org. Biomol. Chem. 2016 14 46 10988 10997 10.1039/C6OB02010K 27827512
    [Google Scholar]
  19. Bettoni L. Seck C. Mbaye M.D. Gaillard S. Renaud J.L. Iron-catalyzed tandem three-component alkylation: Access to α-methylated substituted ketones. Org. Lett. 2019 21 9 3057 3061 10.1021/acs.orglett.9b00630 31017447
    [Google Scholar]
  20. Rammohan A. Reddy J.S. Sravya G. Rao C.N. Zyryanov G.V. Chalcone synthesis, properties and medicinal applications: A review. Environ. Chem. Lett. 2020 18 2 433 458 10.1007/s10311‑019‑00959‑w
    [Google Scholar]
  21. Shalaby M.A. Rizk S.A. Fahim A.M. Synthesis, reactions and application of chalcones: A systematic review. Org. Biomol. Chem. 2023 21 26 5317 5346 10.1039/D3OB00792H 37338020
    [Google Scholar]
  22. Karthikeyan C. Narayana Moorthy N.S.H. Ramasamy S. Vanam U. Manivannan E. Karunagaran D. Trivedi P. Advances in chalcones with anticancer activities. Recent Patents Anticancer Drug Discov. 2014 10 1 97 115 10.2174/1574892809666140819153902 25138130
    [Google Scholar]
  23. Leite F.F. de Sousa N.F. de Oliveira B.H.M. Duarte G.D. Ferreira M.D.L. Scotti M.T. Filho J.M.B. Rodrigues L.C. de Moura R.O. Mendonça-Junior F.J.B. Scotti L. Anticancer activity of chalcones and its derivatives: Review and in silico studies. Molecules 2023 28 10 4009 10.3390/molecules28104009 37241750
    [Google Scholar]
  24. Ma L. Ma R. Wang Y. Zhu X. Zhang J. Chan H.C. Chen X. Zhang W. Chiu S.K. Zhu G. Chalcoplatin, a dual-targeting and p53 activator-containing anticancer platinum(iv) prodrug with unique mode of action. Chem. Commun. (Camb.) 2015 51 29 6301 6304 10.1039/C4CC10409A 25644651
    [Google Scholar]
  25. Bhosle M.R. Deshmukh A.R. Pal S. Srivastava A.K. Mane R.A. Synthesis of new thiazolylmethoxyphenyl pyrimidines and antihyperglycemic evaluation of the pyrimidines, analogues isoxazolines and pyrazolines. Bioorg. Med. Chem. Lett. 2015 25 11 2442 2446 10.1016/j.bmcl.2015.03.068 25937008
    [Google Scholar]
  26. Zhang T. Liu Y. Xin H. Tian J. Deng T. Meng K. An Y. Xue W. Synthesis and antifungal activity of chalcone derivatives containing 1,3,4‐Thiadiazole. Chem. Biodivers. 2024 21 8 202401031 10.1002/cbdv.202401031 38769733
    [Google Scholar]
  27. Greenwald R.B. Zhao H. Reddy P. Synthesis, isolation, and characterization of 2′-paclitaxel glycinate: An application of the Bsmoc protecting group. J. Org. Chem. 2003 68 12 4894 4896 10.1021/jo034077s 12790596
    [Google Scholar]
  28. Lu S. Xia R. Wang J. Pei Q. Xie Z. Jing X. Engineering paclitaxel prodrug nanoparticles via redox-activatable linkage and effective carriers for enhanced chemotherapy. ACS Appl. Mater. Interfaces 2021 13 39 46291 46302 10.1021/acsami.1c12353 34558902
    [Google Scholar]
  29. Dai Y. Zhang Y. Ye T. Chen Y. Synthesis and antitumor evaluation of biotin-SN38-valproic acid conjugates. Molecules 2023 28 9 3936 10.3390/molecules28093936 37175346
    [Google Scholar]
  30. Alalawy A.I. Key genes and molecular mechanisms related to Paclitaxel Resistance. Cancer Cell Int. 2024 24 1 244 10.1186/s12935‑024‑03415‑0 39003454
    [Google Scholar]
  31. Škubník J. Svobodová Pavlíčková V. Ruml T. Rimpelová S. Autophagy in cancer resistance to paclitaxel: Development of combination strategies. Biomed. Pharmacother. 2023 161 114458 10.1016/j.biopha.2023.114458 36889112
    [Google Scholar]
  32. Hashemi M. Zandieh M.A. Talebi Y. Rahmanian P. Shafiee S.S. Nejad M.M. Babaei R. Sadi F.H. Rajabi R. Abkenar Z.O. Rezaei S. Ren J. Nabavi N. Khorrami R. Rashidi M. Hushmandi K. Entezari M. Taheriazam A. Paclitaxel and docetaxel resistance in prostate cancer: Molecular mechanisms and possible therapeutic strategies. Biomed. Pharmacother. 2023 160 114392 10.1016/j.biopha.2023.114392 36804123
    [Google Scholar]
  33. Zaib S. Khan I. Hayyat A. Ali N. Gul A. Naveed M. Role of mitochondrial membrane potential and lactate dehydrogenase A in apoptosis. Anticancer. Agents Med. Chem. 2022 22 11 2048 2062 10.2174/1871520621666211126090906 34825878
    [Google Scholar]
  34. Ly J.D. Grubb D.R. Lawen A. The mitochondrial membrane potential (deltapsi(m)) in apoptosis; An update. Apoptosis 2003 8 2 115 128 10.1023/A:1022945107762 12766472
    [Google Scholar]
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The Conjugation of Paclitaxel with Chalcones for Enhancing Anti-tumor Activity
Bentham Science Publishers ; https://doi.org/10.2174/0115701794395003250725111929
/content/journals/cos/10.2174/0115701794395003250725111929
/content/journals/cos/10.2174/0115701794395003250725111929
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  • Article Type:     Research Article
Keywords: Paclitaxel, chalone, conjugate, synthesis, anticancer ; activity

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