• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利：CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法，用中文像聊天一样搜索，搜遍4000万医学文献。AI智能推荐，让科研检索更轻松。

立即免费搜索

文件翻译

保留排版，准确专业，支持PDF/Word/PPT等文件格式，支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述，25分钟生成高质量综述，智能提取关键信息，辅助科研写作。

立即免费体验

发现并优化麦角甾醇过氧化物衍生物作为新型谷氨酰胺酶 1 抑制剂用于治疗三阴性乳腺癌。

Discovery and Optimization of Ergosterol Peroxide Derivatives as Novel Glutaminase 1 Inhibitors for the Treatment of Triple-Negative Breast Cancer.

机构信息

College of Pharmacy, Qiqihar Medical University, Qiqihar 161006, China.

College of Pharmacy, Hainan University, Haikou 570228, China.

出版信息

Molecules. 2024 Sep 14;29(18):4375. doi: 10.3390/molecules29184375.

DOI:10.3390/molecules29184375
PMID:39339370
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11434480/
Abstract

In this study, novel ergosterol peroxide (EP) derivatives were synthesized and evaluated to assess their antiproliferative activity against four human cancer cell lines (A549, HepG2, MCF-7, and MDA-MB-231). Compound exhibited the most potent antiproliferative activity, with an IC value of 3.20 µM against MDA-MB-231. This value was 5.4-fold higher than that of the parental EP. Bioassay optimization further identified as a novel glutaminase 1 (GLS1) inhibitor (IC = 3.77 µM). In MDA-MB-231 cells, reduced the cellular glutamate levels by blocking the glutamine hydrolysis pathway, which triggered reactive oxygen species production and induced caspase-dependent apoptosis. Molecular docking indicated that interacts with the reaction site of the variable binding pocket by forming multiple interactions with GLS1. In a mouse model of breast cancer, showed remarkable therapeutic effects at a dose of 50 mg/kg, with no apparent toxicity. Based on these results, could be further evaluated as a novel GLS1 inhibitor for triple-negative breast cancer (TNBC) therapy.

摘要

在这项研究中，合成了新型麦角甾醇过氧化物 (EP) 衍生物，并对其进行了评估，以评估它们对四种人癌细胞系 (A549、HepG2、MCF-7 和 MDA-MB-231) 的抗增殖活性。化合物 表现出最强的抗增殖活性，对 MDA-MB-231 的 IC 值为 3.20 µM。这一数值是母体 EP 的 5.4 倍。生物测定优化进一步将 鉴定为新型谷氨酰胺酶 1 (GLS1) 抑制剂（IC = 3.77 µM）。在 MDA-MB-231 细胞中， 通过阻断谷氨酰胺水解途径降低细胞内谷氨酸水平，从而触发活性氧的产生并诱导半胱天冬酶依赖性细胞凋亡。分子对接表明， 通过与 GLS1 的可变结合口袋的反应位点形成多种相互作用来相互作用。在乳腺癌小鼠模型中， 以 50 mg/kg 的剂量表现出显著的治疗效果，且无明显毒性。基于这些结果， 可以进一步评估为三阴性乳腺癌 (TNBC) 治疗的新型 GLS1 抑制剂。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/3ac4484d878e/molecules-29-04375-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/21b85d083103/molecules-29-04375-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/e2cad58bf881/molecules-29-04375-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/4bbe3ac74b4f/molecules-29-04375-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/9f7132b35f2e/molecules-29-04375-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/794cba23dd75/molecules-29-04375-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/bf88b109c816/molecules-29-04375-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/894aad7d95e6/molecules-29-04375-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/0dfb1b26ea47/molecules-29-04375-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/03d12d87d11a/molecules-29-04375-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/3ac4484d878e/molecules-29-04375-g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/21b85d083103/molecules-29-04375-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/e2cad58bf881/molecules-29-04375-sch001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/4bbe3ac74b4f/molecules-29-04375-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/9f7132b35f2e/molecules-29-04375-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/794cba23dd75/molecules-29-04375-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/bf88b109c816/molecules-29-04375-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/894aad7d95e6/molecules-29-04375-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/0dfb1b26ea47/molecules-29-04375-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/03d12d87d11a/molecules-29-04375-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e381/11434480/3ac4484d878e/molecules-29-04375-g009.jpg

相似文献

1
Discovery and Optimization of Ergosterol Peroxide Derivatives as Novel Glutaminase 1 Inhibitors for the Treatment of Triple-Negative Breast Cancer.发现并优化麦角甾醇过氧化物衍生物作为新型谷氨酰胺酶 1 抑制剂用于治疗三阴性乳腺癌。
Molecules. 2024 Sep 14;29(18):4375. doi: 10.3390/molecules29184375.
2
Discovery and optimization of withangulatin A derivatives as novel glutaminase 1 inhibitors for the treatment of triple-negative breast cancer.发现并优化 withangulatin A 衍生物作为新型谷氨酰胺酶 1 抑制剂用于治疗三阴性乳腺癌。
Eur J Med Chem. 2021 Jan 15;210:112980. doi: 10.1016/j.ejmech.2020.112980. Epub 2020 Nov 1.
3
Discovery of novel 1,8-naphthalimide piperazinamide based benzenesulfonamides derivatives as potent carbonic anhydrase IX inhibitors and ferroptosis inducers for the treatment of triple-negative breast cancer.发现新型 1,8-萘酰亚胺哌嗪酰胺苯磺酰胺衍生物作为有效的碳酸酐酶 IX 抑制剂和铁死亡诱导剂，用于治疗三阴性乳腺癌。
Bioorg Chem. 2024 Sep;150:107596. doi: 10.1016/j.bioorg.2024.107596. Epub 2024 Jun 26.
4
Antitumor activity of the glutaminase inhibitor CB-839 in triple-negative breast cancer.谷氨酰胺酶抑制剂CB-839在三阴性乳腺癌中的抗肿瘤活性。
Mol Cancer Ther. 2014 Apr;13(4):890-901. doi: 10.1158/1535-7163.MCT-13-0870. Epub 2014 Feb 12.
5
Characterization of HJ-PI01 as a novel Pim-2 inhibitor that induces apoptosis and autophagic cell death in triple-negative human breast cancer.HJ-PI01作为一种新型Pim-2抑制剂的特性研究，该抑制剂可诱导三阴性人类乳腺癌细胞凋亡和自噬性细胞死亡。
Acta Pharmacol Sin. 2016 Sep;37(9):1237-50. doi: 10.1038/aps.2016.60. Epub 2016 Jul 11.
6
Development of ergosterol peroxide probes for cellular localisation studies.过氧麦角甾醇探针的研制及其用于细胞定位研究。
Org Biomol Chem. 2019 May 29;17(21):5223-5229. doi: 10.1039/c9ob00145j.
7
LLY17, a novel small molecule STAT3 inhibitor induces apoptosis and suppresses cell migration and tumor growth in triple-negative breast cancer.LLY17，一种新型小分子 STAT3 抑制剂，可诱导三阴性乳腺癌细胞凋亡，抑制细胞迁移和肿瘤生长。
Breast Cancer Res Treat. 2020 May;181(1):31-41. doi: 10.1007/s10549-020-05613-6. Epub 2020 Apr 2.
8
[Anti-breast cancer effect of a mitochondrion-targeted derivative of ergosterol peroxide in vitro and in vivo].[麦角甾醇过氧化物线粒体靶向衍生物的体内外抗乳腺癌作用]
Zhongguo Zhong Yao Za Zhi. 2024 Aug;49(15):4139-4147. doi: 10.19540/j.cnki.cjcmm.20240402.403.
9
Design, synthesis and docking studies of novel 4-aminophenol-1,2,4-oxadiazole hybrids as apoptosis inducers against triple negative breast cancer cells targeting MAP kinase.新型 4-氨基酚-1,2,4-恶二唑杂合体的设计、合成及对接研究，作为针对 MAP 激酶的三阴性乳腺癌细胞凋亡诱导剂。
J Biomol Struct Dyn. 2024 Jul;42(11):5841-5857. doi: 10.1080/07391102.2023.2239912. Epub 2023 Aug 2.
10
Novel indole Schiff base β-diiminato compound as an anti-cancer agent against triple-negative breast cancer: In vitro anticancer activity evaluation and in vivo acute toxicity study.新型吲哚席夫碱β-二亚胺化合物作为一种针对三阴性乳腺癌的抗癌剂：体外抗癌活性评价和体内急性毒性研究。
Bioorg Chem. 2024 Nov;152:107730. doi: 10.1016/j.bioorg.2024.107730. Epub 2024 Aug 16.

本文引用的文献

1
Glutamine metabolism in tumor metastasis: Genes, mechanisms and the therapeutic targets.肿瘤转移中的谷氨酰胺代谢：基因、机制及治疗靶点
Heliyon. 2023 Oct 5;9(10):e20656. doi: 10.1016/j.heliyon.2023.e20656. eCollection 2023 Oct.
2
Molecular mechanisms of ROS-modulated cancer chemoresistance and therapeutic strategies.ROS 调控的癌症化疗耐药性的分子机制及治疗策略。
Biomed Pharmacother. 2023 Sep;165:115036. doi: 10.1016/j.biopha.2023.115036. Epub 2023 Jun 22.
3
Targeting glutamine metabolism as a therapeutic strategy for cancer.
针对谷氨酰胺代谢作为癌症治疗策略。
Exp Mol Med. 2023 Apr;55(4):706-715. doi: 10.1038/s12276-023-00971-9. Epub 2023 Apr 3.
4
Triple-Negative Breast Cancer: A Review of Current Curative Intent Therapies.三阴性乳腺癌：当前治愈性意图治疗的综述。
Curr Oncol. 2022 Jul 7;29(7):4768-4778. doi: 10.3390/curroncol29070378.
5
Effects of Glucose Metabolism, Lipid Metabolism, and Glutamine Metabolism on Tumor Microenvironment and Clinical Implications.糖代谢、脂代谢与谷氨酰胺代谢对肿瘤微环境的影响及其临床意义
Biomolecules. 2022 Apr 14;12(4):580. doi: 10.3390/biom12040580.
6
Filamentous GLS1 promotes ROS-induced apoptosis upon glutamine deprivation via insufficient asparagine synthesis.丝状 GLS1 通过谷氨酰胺剥夺时天冬酰胺合成不足促进 ROS 诱导的细胞凋亡。
Mol Cell. 2022 May 19;82(10):1821-1835.e6. doi: 10.1016/j.molcel.2022.03.016. Epub 2022 Apr 4.
7
Recent Advances in the Synthetic Biology of Natural Drugs.天然药物合成生物学的最新进展
Front Bioeng Biotechnol. 2021 Jul 29;9:691152. doi: 10.3389/fbioe.2021.691152. eCollection 2021.
8
Targeting glutamine dependence through GLS1 inhibition suppresses ARID1A-inactivated clear cell ovarian carcinoma.通过抑制谷氨酰胺酶1（GLS1）靶向谷氨酰胺依赖性可抑制ARID1A失活的透明细胞卵巢癌。
Nat Cancer. 2021 Feb;2(2):189-200. doi: 10.1038/s43018-020-00160-x. Epub 2021 Jan 11.
9
Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells.抑制 eEF2K 与谷氨酰胺酶抑制剂或 4EBP1 耗竭协同作用，抑制三阴性乳腺癌细胞的生长。
Sci Rep. 2021 Apr 28;11(1):9181. doi: 10.1038/s41598-021-88816-1.
10
Ergosterol peroxide exhibits antiviral and immunomodulatory abilities against porcine deltacoronavirus (PDCoV) via suppression of NF-κB and p38/MAPK signaling pathways in vitro.麦角甾醇过氧化物通过体外抑制 NF-κB 和 p38/MAPK 信号通路表现出抗猪德尔塔冠状病毒（PDCoV）的抗病毒和免疫调节能力。
Int Immunopharmacol. 2021 Apr;93:107317. doi: 10.1016/j.intimp.2020.107317. Epub 2021 Jan 22.