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

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

Abstract

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.