Biselyngbyolide B 的结构-活性关系研究揭示了线粒体分裂诱导的癌症细胞毒性

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-04-19 DOI:10.1021/acsmedchemlett.4c00094

Pratiti Mandal, Debobrata Paul, Himangshu Sharma, Sanu Saha, Partha Chakrabarti* and Rajib Kumar Goswami*,

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引用次数: 0

摘要

对强效抗癌海洋大环内酯 biselyngbyolide B 进行了系统的结构-活性关系研究。针对人类结直肠癌细胞系，研究了母体天然产物的总共 11 种结构变体，其中 2 种是天然类似物。母体分子中负责细胞毒性活性的必要功能单元已被披露。Biselyngbyolide C 是 Biselyngbyolide B 的天然类似物之一，我们对其进行了深入研究，以探索其分子机制。有趣的是，体外研究数据表明，诱导达因明相关蛋白 1 介导的线粒体裂变和活性氧产生，从而激活 ASK1/P38/JNK 介导的结肠癌细胞凋亡，这是 Biselyngbyolide B 介导细胞毒性的重要途径。值得注意的是，这项研究揭示了一种大环内酯类药物参与线粒体裂变以促进癌细胞凋亡，为我们提供了新的认识。

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Structure–Activity Relationship Study of Biselyngbyolide B Reveals Mitochondrial Fission-Induced Cytotoxicity in Cancer

A systematic structure–activity relationship study of the potent anticancer marine macrolide biselyngbyolide B has been accomplished. A total of 11 structural variants of the parent natural product, of which 2 are natural analogues, have been studied against a human colorectal carcinoma cell line. The requisite functional units of the parent molecule responsible for the cytotoxic activities have been disclosed. Biselyngbyolide C, one of the natural analogues of biselyngbyolide B, has been studied in depth to explore its molecular mechanism. Interestingly, the in vitro data demonstrated an induction of dynamin-related protein 1-mediated mitochondrial fission and reactive oxygen species production which led to activation of ASK1/P38/JNK-mediated apoptosis in colon cancer cells as an important pathway for biselyngbyolide B-mediated cytotoxicity. Notably, this study revealed that a macrolide participated in mitochondrial fission to promote apoptosis of cancer cells, providing new insight.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.