青藤碱衍生物3a代谢物中的新化合物3a- m1通过IP3R/ orai介导的CTL凋亡发挥有效的抗再生障碍性贫血活性

IF 6.8 1区医学 Q1 CHEMISTRY, MEDICINAL

Journal of Medicinal Chemistry Pub Date : 2025-04-17 DOI:10.1021/acs.jmedchem.5c00546

Ziqian Zhang, Xilan Ma, Wei Pan, Xiaoshun Li, Yanyan Li, Nan Fang, Xin Yin, Longlong Yang, Qi Hou, Dezhi Yang, Tengfei Ji, Ruifang Zheng, Mingbao Lin

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引用次数: 0

摘要

再生障碍性贫血（AA）是一种治疗效果有限且副作用严重的难治性血液病。细胞毒性T淋巴细胞（ctl）在AA发病中起关键作用。在我们之前的研究中，我们获得了青藤碱衍生物3a，它以低毒性的ctl为靶点，具有潜在的抗aa活性。本研究从3a代谢中鉴定出一种新的代谢物3a- m1，具有优化的生物利用度，在免疫介导的骨髓衰竭小鼠模型中，该代谢物在缓解贫血症状、抑制骨髓ctl活化、改善造血功能方面表现出更为显著的作用。体外实验表明，3a-M1直接抑制ctl的活化及其杀伤功能；其潜在机制至少在一定程度上是通过IP3R/ORAI途径介导的过度激活的ctl选择性铁凋亡。这些发现表明，3a-M1是一种新的潜在的AA治疗药物，铁下垂可能是ctl治疗AA的一个有希望的靶点。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

A Novel Compound 3a-M1, from Metabolites of Sinomenine Derivative 3a, Exerts Potent Anti-Aplastic Anemia Activity via IP3R/ORAI-Mediated CTL Ferroptosis

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A Novel Compound 3a-M1, from Metabolites of Sinomenine Derivative 3a, Exerts Potent Anti-Aplastic Anemia Activity via IP3R/ORAI-Mediated CTL Ferroptosis

Aplastic anemia (AA) is a refractory hematological disease with limited therapeutic effectiveness and serious treatment-related side effects. Cytotoxic T lymphocytes (CTLs) play a key role in AA pathogenesis. In our previous study, sinomenine derivative 3a was obtained, which demonstrated potential anti-AA activity by targeting CTLs with low toxicity. In this study, a novel metabolite, 3a-M1, was identified with optimized bioavailability from 3a metabolism, which exhibited a more notable effect in alleviating anemia symptoms, suppressing bone marrow CTLs activation, and improving hematopoietic function in immune-mediated bone marrow failure mouse models. In vitro experiments demonstrated that 3a-M1 directly inhibited CTLs activation and their killing function; the underlying mechanism was at least in part mediated by the selective ferroptosis of overactivated CTLs via the IP₃R/ORAI pathway. These findings suggest that 3a-M1 represents a novel potential therapeutic agent for AA treatment and ferroptosis may serve as a promising target on CTLs for AA therapy.

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来源期刊

Journal of Medicinal Chemistry 医学-医药化学

CiteScore

4.00

自引率

11.00%

发文量

804

审稿时长

1.9 months

期刊介绍： The Journal of Medicinal Chemistry is a prestigious biweekly peer-reviewed publication that focuses on the multifaceted field of medicinal chemistry. Since its inception in 1959 as the Journal of Medicinal and Pharmaceutical Chemistry, it has evolved to become a cornerstone in the dissemination of research findings related to the design, synthesis, and development of therapeutic agents. The Journal of Medicinal Chemistry is recognized for its significant impact in the scientific community, as evidenced by its 2022 impact factor of 7.3. This metric reflects the journal's influence and the importance of its content in shaping the future of drug discovery and development. The journal serves as a vital resource for chemists, pharmacologists, and other researchers interested in the molecular mechanisms of drug action and the optimization of therapeutic compounds.