{"title":"Design and synthesis of 3,4-<i>seco</i>-Lupane triterpene derivatives: targeting tumor angiogenesis and inducing apoptosis in triple-negative breast cancer.","authors":"Chunyu Gao, Hongbo Teng, Wenxin Zhang, Yaru Zhao, Chunguo Cui, Zerbo Patrice, Liyan Wang, Yan Zhao","doi":"10.3389/fchem.2025.1630939","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>Due to the lack of effective treatment methods and targeted drugs, triple-negative breast cancer (TNBC) is not only difficult to treat clinically, but also has a poor prognosis for patients. This study aims to develop novel anti-TNBC drug candidates by designing 90 derivatives of 3,4-<i>seco</i>-lupane triterpene derivatives, a natural product of the genus Eleutherogenus.</p><p><strong>Methods: </strong>Firstly, 90 derivatives were synthesized and screened, and the compound I-27 showed excellent cytotoxicity (IC<sub>50</sub>=1.02 μM) for MDA-MB-231 cells for further activity verification. Then in vitro tests were carried out to detect the effects of the compound on the proliferation, migration, invasion and apoptosis of TNBC cells. With the help of transcriptomics, the mechanism of action was explored and verified. At the same time, its inhibitory effect on tumor volume and lung metastasis was verified through a mouse model of in vivo test, and its mechanism of action was further verified.</p><p><strong>Results: </strong>In vitro tests showed that compound I.-27 could effectively inhibit the proliferation, migration and invasion of TNBC cells, and induce apoptosis. Transcriptomic analysis revealed that it has a dual mechanism of action. On the one hand, it inhibits tumor angiogenesis through the ID1/TSP-1 pathway. On the other hand, it promotes apoptosis through the PI3K/AKT/FoxO1 signaling pathway. In vivo tests, the compound significantly reduced tumor volume and inhibited lung metastasis through mouse models. It further confirmed that ID1 is a key target for anti-tumor.</p><p><strong>Conclusions: </strong>In this study, an anti-TNBC drug with multiple mechanisms was developed from the triterpenoids of 3,4-3,4-<i>seco</i>-lupane triterpene derivatives for the first time, and the mechanism of action was clarified by combining transcriptomics, molecular docking and gene knockout technologies. Compound I-27 provides a potential breakthrough for the treatment of triple-negative breast cancer as a potential therapeutic candidate with a novel action mechanism and high potency.</p>","PeriodicalId":12421,"journal":{"name":"Frontiers in Chemistry","volume":"13 ","pages":"1630939"},"PeriodicalIF":4.2000,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12351286/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Frontiers in Chemistry","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.3389/fchem.2025.1630939","RegionNum":3,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/1 0:00:00","PubModel":"eCollection","JCR":"Q2","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: Due to the lack of effective treatment methods and targeted drugs, triple-negative breast cancer (TNBC) is not only difficult to treat clinically, but also has a poor prognosis for patients. This study aims to develop novel anti-TNBC drug candidates by designing 90 derivatives of 3,4-seco-lupane triterpene derivatives, a natural product of the genus Eleutherogenus.
Methods: Firstly, 90 derivatives were synthesized and screened, and the compound I-27 showed excellent cytotoxicity (IC50=1.02 μM) for MDA-MB-231 cells for further activity verification. Then in vitro tests were carried out to detect the effects of the compound on the proliferation, migration, invasion and apoptosis of TNBC cells. With the help of transcriptomics, the mechanism of action was explored and verified. At the same time, its inhibitory effect on tumor volume and lung metastasis was verified through a mouse model of in vivo test, and its mechanism of action was further verified.
Results: In vitro tests showed that compound I.-27 could effectively inhibit the proliferation, migration and invasion of TNBC cells, and induce apoptosis. Transcriptomic analysis revealed that it has a dual mechanism of action. On the one hand, it inhibits tumor angiogenesis through the ID1/TSP-1 pathway. On the other hand, it promotes apoptosis through the PI3K/AKT/FoxO1 signaling pathway. In vivo tests, the compound significantly reduced tumor volume and inhibited lung metastasis through mouse models. It further confirmed that ID1 is a key target for anti-tumor.
Conclusions: In this study, an anti-TNBC drug with multiple mechanisms was developed from the triterpenoids of 3,4-3,4-seco-lupane triterpene derivatives for the first time, and the mechanism of action was clarified by combining transcriptomics, molecular docking and gene knockout technologies. Compound I-27 provides a potential breakthrough for the treatment of triple-negative breast cancer as a potential therapeutic candidate with a novel action mechanism and high potency.
期刊介绍：
Frontiers in Chemistry is a high visiblity and quality journal, publishing rigorously peer-reviewed research across the chemical sciences. Field Chief Editor Steve Suib at the University of Connecticut is supported by an outstanding Editorial Board of international researchers. This multidisciplinary open-access journal is at the forefront of disseminating and communicating scientific knowledge and impactful discoveries to academics, industry leaders and the public worldwide.
Chemistry is a branch of science that is linked to all other main fields of research. The omnipresence of Chemistry is apparent in our everyday lives from the electronic devices that we all use to communicate, to foods we eat, to our health and well-being, to the different forms of energy that we use. While there are many subtopics and specialties of Chemistry, the fundamental link in all these areas is how atoms, ions, and molecules come together and come apart in what some have come to call the “dance of life”.
All specialty sections of Frontiers in Chemistry are open-access with the goal of publishing outstanding research publications, review articles, commentaries, and ideas about various aspects of Chemistry. The past forms of publication often have specific subdisciplines, most commonly of analytical, inorganic, organic and physical chemistries, but these days those lines and boxes are quite blurry and the silos of those disciplines appear to be eroding. Chemistry is important to both fundamental and applied areas of research and manufacturing, and indeed the outlines of academic versus industrial research are also often artificial. Collaborative research across all specialty areas of Chemistry is highly encouraged and supported as we move forward. These are exciting times and the field of Chemistry is an important and significant contributor to our collective knowledge.
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