ORIGINAL RESEARCH article
Front. Chem.
Sec. Medicinal and Pharmaceutical Chemistry
Volume 13 - 2025 | doi: 10.3389/fchem.2025.1630939
This article is part of the Research TopicInterdisciplinary Approaches for Uncovering the Anti-tumor Mechanisms of Chinese Drugs and Natural ProductsView all 3 articles
Design and Synthesis of 3,4-Seco-Lupane Triterpene Derivatives: Targeting Tumor Angiogenesis and Inducing Apoptosis in Triple-Negative Breast Cancer
Provisionally accepted
- 1Jilin Agriculture University, Changchun, China
- 2Breast Surgery Department of Bethune Third Hospital, Jilin University, Changchun, China
- 3Département: Biochimie / Microbiologie UFR Sciences de la Vie et de la Terre, 03 BP 7021 Ouagadougou 03, Burkina Faso, Ouagadougou, Burkina Faso
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Triple-negative breast cancer (TNBC) poses significant therapeutic challenges due to the lack of effective targets, leading to poor prognosis. This study developed a novel anti-TNBC candidate by designing 90 derivatives of 3,4-seco-lupane triterpenoid chiisanogenin, a natural product from Acanthopanax species. Compound Ⅰ-27 exhibited superior cytotoxicity (IC50 = 1.02 μM against MDA-MB-231 cells) and was selected for mechanistic evaluation. In vitro assays revealed that compound Ⅰ-27 suppressed TNBC cell proliferation, migration, invasion, and induced apoptosis. Transcriptomics and molecular analyses demonstrated its dual mechanisms: inhibiting tumor angiogenesis via the ID1/TSP-1 pathway and promoting apoptosis through PI3K/AKT/FoxO1 signaling. In vivo, compound Ⅰ-27 (20 mg/kg) markedly reduced tumor volume and lung metastasis in murine models, with efficacy comparable to doxorubicin. This study for the first time developed a dual-pathway anti-TNBC drug from oleanolic acid derivatives, and simultaneously clarified the mechanism of synergistic action by combining transcriptomics and molecular docking techniques. Finally, the knockout experiment verified that ID1 is the key target. This research highlights compound Ⅰ-27 as a promising therapeutic candidate with a novel mechanism and high efficacy, providing a potential breakthrough for the treatment of triplenegative breast cancer.
Keywords: seco-lupane triterpene derivatives, Triple-negative breast cancer, Transcriptomics, Apoptosis, Angiogenesis
Received: 19 May 2025; Accepted: 09 Jul 2025.
Copyright: © 2025 Gao, Teng, Zhang, Zhao, Cui, Patrice, Zhao and Wang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Liyan Wang, Jilin Agriculture University, Changchun, China
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