2. Academic Validation
  3. Discovery of novel combretastatin A4 derivatives as a microtubule targeting agent capable of inducing HepG-2 cell apoptosis via the mitochondria and ER stress mediated pathway

Discovery of novel combretastatin A4 derivatives as a microtubule targeting agent capable of inducing HepG-2 cell apoptosis via the mitochondria and ER stress mediated pathway

  • Bioorg Chem. 2025 Jun 6:163:108676. doi: 10.1016/j.bioorg.2025.108676.
Xiaochao Huang 1,  Juping Tang 2,  Nan Xu 3,  Wentian Zhong 2,  Guimei Li 2,  Yuanhang Chen 3,  Yi Jing 3,  Yong Yang 3,  Zhikun Liu 4,  Meng Wang 5,  Hengshan Wang 6
Affiliations

Affiliations

  • 1 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Huaiyin Institute of Technology, Huai'an 223003, China; Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China.
  • 2 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China.
  • 3 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Huaiyin Institute of Technology, Huai'an 223003, China.
  • 4 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Huaiyin Institute of Technology, Huai'an 223003, China. Electronic address: ytdxliuzhikun1@163.com.
  • 5 National & Local Joint Engineering Research Center for Mineral Salt Deep Utilization, Jiangsu Key Laboratory of Regional Specific Resource Pharmaceutical Transformation, Huaiyin Institute of Technology, Huai'an 223003, China; Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China. Electronic address: vipmengwang@126.com.
  • 6 Key Laboratory for Chemistry and Molecular Engineering of Medicinal Resources (Ministry of Education of China), Guangxi Key Laboratory of Chemistry and Molecular Engineering of Medicinal Resources, School of Chemistry and Pharmaceutical Sciences, Guangxi Normal University, Guilin, 541004, China. Electronic address: whengshan@163.com.
PMID: 40516170 DOI: 10.1016/j.bioorg.2025.108676
Abstract

Microtubule-targeting agents, such as paclitaxel and docetaxel, have been extensively utilized as clinically effective chemotherapeutic agents for Cancer treatment. However, their efficacy may be impeded by the acquired or intrinsic resistance of tumor cells to Apoptosis, in addition to their high toxicity toward normal human cells or tissues. Herein, seventeen CA-4 analogues were synthesized and characterized, followed by investigation of their antiproliferative activity using MTT assays. Among them, compound 9n exhibited the best antitumor activity against a panel of tested Cancer cell lines including drug resistance cells A549/CDDP, A549/paclitaxel and MCF-7/DOX, respectively, with IC50 values ranging from 0.09 to 0.51 μM, and accordingly showed low toxicity toward normal liver cells HL-7702. Mechanistic studies suggested that compound 9n not only significantly inhibited tubulin polymerization and cell migration and invasion, but also effectively triggered HepG-2 cells Apoptosis through the mitochondria and ER stress mediated pathway. More importantly, in HepG-2 xenograft models, compound 9n achieved 70.7 % of the antitumor inhibition rate at dose of 30 mg/kg and without obvious systemic toxicity, and accordingly exceeding to that of CA-4 (61.2 %@15 mg/kg). Collectively, these results demonstrated that compound 9n, as a promising tubulin inhibitor, has great potential for the Cancer therapy.

Keywords

Antitumor; Apoptosis; CA-4; Tubulin.

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