Discovery of dimeric costunolide-triazole conjugates as antihepatoma agents via integrating dimerization and molecular hybridization

Keywords

Antihepatoma activity / Costunolide / Triazole / Dimers / Glucose-6-phosphate dehydrogenase (G6PD) / Mechanism

Funding

This work was supported by the National Natural Science Foundation of China (Nos. 22137008 and 82473809), the Xingdian Yingcai Project (No. YNWR-KJLJ-2019-002), the Reserve Talents of Young and Middle-aged Academic and Technical Leaders in Yunnan Province (No. 202105AC160021), and the Yunnan Fundamental Research Projects (No. 202401AS070077).

Declaration of competing interest

These authors have no conflict of interest to declare.

Supporting information

NMR and MS data for compounds 1−37, original figures of Western blot (PDF) can be requested by sending E-mail to the corresponding author.

References

[1] Zheng J, Wang S, Xia L, et al. Hepatocellular carcinoma: signaling pathways and therapeutic advances. Signal Transduct Target Ther. 2025; 10(1):35. https://doi.org/10.1038/s41392-024-02075-w.

[2] Singh SP, Madke T, Chand P. Global epidemiology of hepatocellular carcinoma. J Clin Exp Hepatol. 2025; 15(2):102446. https://doi.org/10.1016/j.jceh.2024.102446.

[3] Asma ST, Acaroz U, Imre K, et al. Natural products/bioactive compounds as a source of anticancer drugs. Cancers. 2022; 14(24):6203. https://doi.org/10.3390/cancers14246203.

[4] Kim DY, Choi BY. Costunolide—a bioactive sesquiterpene lactone with diverse therapeutic potential. Int J Mol Sci. 2019; 20(12):2926. https://doi.org/10.3390/ijms20122926.

[5] Lin X, Peng Z, Su C. Potential anti-cancer activities and mechanisms of costunolide and dehydrocostuslactone. Int J Mol Sci. 2015; 16(5):10888-10906. https://doi.org/10.3390/ijms160510888.

[6] Vadaparthi PRR, Pavan KC, Kumar K, et al. Synthesis of costunolide derivatives by Pd-catalyzed heck arylation and evaluation of their cytotoxic activities. Med Chem Res. 2015; 24(7):2871-2878. https://doi.org/10.1007/s00044-015-1337-5.

[7] Srivastava SK, Abraham A, Bhat B, et al. Synthesis of 13-amino costunolide derivatives as anticancer agents. Bioorg Med Chem Lett. 2006; 16(16):4195-4199. https://doi.org/10.1016/j.bmcl.2006.05.083.

[8] Pavan KC, Devi A, Ashok YP, et al. “Click” reaction mediated synthesis of costunolide and dehydrocostuslactone derivatives and evaluation of their cytotoxic activity. J Asian Nat Prod Res. 2016; 18(11):1063-1078. https://doi.org/10.1080/10286020.2016.1193012.

[9] Su L, Zhang X, Ma Y, et al. New guaiane-type sesquiterpenoid dimers from Artemisia atrovirens and their antihepatoma activity. Acta Pharm Sin B. 2021; 11(6):1648-1666. https://doi.org/10.1016/j.apsb.2020.12.006.

[10] Su LH, Ma WJ, Ma YB, et al. Artemiprincepsolides A-F, novel germacrane-guaiane and eudesmane-guaiane sesquiterpenoid dimers from Artemisia princeps and their antihepatoma activity. Chin J Chem. 2023; 41(20):2648-2656. https://doi.org/10.1002/cjoc.202300242.

[11] Su LH, Ma WJ, Ma YB, et al. Artemiprinolides A-M, thirteen undescribed sesquiterpenoid dimers from Artemisia princeps and their antihepatoma activity. Phytochemistry. 2023; 211:113714. https://doi.org/10.1016/j.phytochem.2023.113714.

[12] He X, Ma W, Hu J, et al. Diverse structures and antihepatoma effect of sesquiterpenoid dimers from Artemisia eriopoda by AKT/STAT signaling pathway. Signal Transduct Target Ther. 2023; 8(1):64. https://doi.org/10.1038/s41392-022-01267-6.

[13] Gao Z, Ma WJ, Li TZ, et al. Artemidubolides A-T, cytotoxic unreported guaiane-type sesquiterpenoid dimers against three hepatoma cell lines from Artemisia dubia. Phytochemistry. 2022; 202:113299. https://doi.org/10.1016/j.phytochem.2022.113299.

[14] Dong W, Ma WJ, Ma YB, et al. Guaiane-type sesquiterpenoid dimers from Artemisia zhongdianensis and antihepatoma carcinoma activity via the p38MAPK pathway. Chin J Chem. 2023; 41(19):2453-2468. https://doi.org/10.1002/cjoc.202300166.

[15] Li TZ, Yang XT, Wang JP, et al. Biomimetic synthesis of lavandiolides H, I, and K and artematrolide F via Diels-Alder reaction. Org Lett. 2021; 23(21):8380-8384. https://doi.org/10.1021/acs.orglett.1c03120.

[16] Yan JX, Li QH, Li TZ, et al. Design and synthesis of guaianolide-germacranolide heterodimers as novel anticancer agents against hepatocellular carcinoma. Drug Dev Res. 2023; 84(6):1285-1298. https://doi.org/10.1002/ddr.22087.

[17] Janganati V, Ponder J, Jordan CT, et al. Dimers of melampomagnolide B exhibit potent anticancer activity against hematological and solid tumor cells. J Med Chem. 2015; 58(22):8896-8906. https://doi.org/10.1021/acs.jmedchem.5b01187.

[18] Ren H, Zhang YY, Li YL, et al. Semisynthesis and non-small-cell lung cancer cytotoxicity evaluation of germacrane-type sesquiterpene lactones from Elephantopus scaber. J Nat Prod. 2022; 85(2):352-364. https://doi.org/10.1021/acs.jnatprod.1c00936.

[19] Li TZ, Yang XT, Ma WJ, et al. Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents. Bioorg Chem. 2023; 137:106617. https://doi.org/10.1016/j.bioorg.2023.106617.

[20] Ding Y, Xue Q, Liu S, et al. Identification of parthenolide dimers as activators of pyruvate kinase M2 in xenografts of glioblastoma multiforme in vivo. J Med Chem. 2020; 63(4):1597-1611. https://doi.org/10.1021/acs.jmedchem.9b01328.

[21] Li TZ, Huang FD, Yan JX, et al. Discovery of dimeric guaianolides with all carbon linkers as potential antihepatoma agents. Eur J Med Chem. 2025; 300:118160. https://doi.org/10.1016/j.ejmech.2025.118160.

[22] de Sena MPP, Franco LS, Montagnoli TL, et al. Molecular hybridization: a powerful tool for multitarget drug discovery. Expert Opin Drug Discov. 2024; 19(4):451-470. https://doi.org/10.1080/17460441.2024.2322990.

[23] Xu Z, Zhao SJ, Liu Y. 1,2,3-Triazole-containing hybrids as potential anticancer agents: current developments, action mechanisms and structure-activity relationships. Eur J Med Chem. 2019; 183:111700. https://doi.org/10.1016/j.ejmech.2019.111700.

[24] Xiao Z, Gu Y, Dong H, et al. Strategic application of CuAAC click chemistry in the modification of natural products for anticancer activity. Eur J Med Chem Rep. 2023; 9:100113. https://doi.org/10.1016/j.ejmcr.2023.100113.

[25] Ding Y, Guo H, Ge W, et al. Copper(I) oxide nanoparticles catalyzed click chemistry based synthesis of melampomagnolide B-triazole conjugates and their anti-cancer activities. Eur J Med Chem. 2018; 156:216-229. https://doi.org/10.1016/j.ejmech.2018.06.058.

[26] Janganati V, Ponder J, Balasubramaniam M, et al. MMB triazole analogs are potent NF-κB inhibitors and anti-cancer agents against both hematological and solid tumor cells. Eur J Med Chem. 2018; 157:562-581. https://doi.org/10.1016/j.ejmech.2018.08.010.

[27] Khazir J, Hyder I, Gayatri JL, et al. Design and synthesis of novel 1,2,3-triazole derivatives of coronopilin as anti-cancer compounds. Eur J Med Chem. 2014; 82:255-262. https://doi.org/10.1016/j.ejmech.2014.05.053.

[28] Wang YC, Li TZ, Chen JJ. Compound-protein interaction prediction based on heterogeneous network reveals potential antihepatoma agents. iScience. 2024; 27(8):110418. https://doi.org/10.1016/j.isci.2024.110418.

[29] Meng Q, Zhang Y, Hao S, et al. Recent findings in the regulation of G6PD and its role in diseases. Front Pharmacol. 2022; 13:932154. https://doi.org/10.3389/fphar.2022.932154.

[30] Lu M, Lu L, Dong Q, et al. Elevated G6PD expression contributes to migration and invasion of hepatocellular carcinoma cells by inducing epithelial-mesenchymal transition. Acta Biochim Biophys Sin (Shanghai). 2018; 50(4):370-380. https://doi.org/10.1093/abbs/gmy009.

[31] Zhang Z, Liew CW, Handy DE, et al. High glucose inhibits glucose-6-phosphate dehydrogenase, leading to increased oxidative stress and β-cell apoptosis. FASEB J. 2010; 24(5):1497-1505. https://doi.org/10.1096/fj.09-136572.

[32] Cao F, Luo A, Yang C. G6PD inhibits ferroptosis in hepatocellular carcinoma by targeting cytochrome P450 oxidoreductase. Cell Signal. 2021; 87:110098. https://doi.org/10.1016/j.cellsig.2021.110098.