{"title":"3,4-二叔环三萜衍生物的设计与合成：靶向三阴性乳腺癌肿瘤血管生成和诱导细胞凋亡。","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":"{\"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. 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引用次数: 0
摘要
背景：由于缺乏有效的治疗方法和靶向药物，三阴性乳腺癌（triple negative breast cancer， TNBC）不仅临床治疗困难，而且患者预后较差。本研究旨在通过设计90种刺荆属天然产物3,4-二-狼烷三萜衍生物，开发新的抗tnbc候选药物。方法：首先合成90个衍生物并进行筛选，化合物I-27对MDA-MB-231细胞具有良好的细胞毒性（IC50=1.02 μM），进一步进行活性验证。体外实验检测该化合物对TNBC细胞增殖、迁移、侵袭和凋亡的影响。在转录组学的帮助下，对其作用机制进行了探索和验证。同时通过小鼠体内实验模型验证其对肿瘤体积和肺转移的抑制作用，并进一步验证其作用机制。结果：体外实验表明，化合物i -27能有效抑制TNBC细胞的增殖、迁移和侵袭，并诱导细胞凋亡。转录组学分析显示其具有双重作用机制。一方面，它通过ID1/TSP-1途径抑制肿瘤血管生成。另一方面，通过PI3K/AKT/FoxO1信号通路促进细胞凋亡。在体内实验中，该化合物通过小鼠模型显著减小肿瘤体积，抑制肺转移。进一步证实了ID1是抗肿瘤的关键靶点。结论：本研究首次从3,4-3,4-二萜三萜衍生物的三萜中开发出一种多机制的抗tnbc药物，并结合转录组学、分子对接和基因敲除技术阐明了其作用机制。化合物I-27作为一种具有新作用机制和高效能的潜在候选药物，为治疗三阴性乳腺癌提供了潜在的突破。
Design and synthesis of 3,4-seco-Lupane triterpene derivatives: targeting tumor angiogenesis and inducing apoptosis in triple-negative breast cancer.
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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