Glioma, a common primary brain tumor, is highly infiltrative and invasive, often leading to drug resistance and recurrence. Therefore, the development of novel therapeutic agents is urgently needed. Pseudellone C is a novel marine triindole alkaloid. Screening of its antiproliferative activity against 55 cell lines revealed its anti-CNS cancer potential. A total of 42 derivatives of Pseudellone C were designed and synthesized, and their inhibitory activities against two human glioma cell lines (U-87MG and LN-229) were evaluated using the CCK-8 assay. Ten derivatives exhibited potent antiproliferative activity with IC values below 10 μmol, which are 18- to 39- fold more potent than Pseudellone C. Among these, derivative demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that induces apoptosis primarily by activating the downstream caspase 3 cascade via the TNF/TNFR pathway. Structure-activity relationship correlations were systematically analyzed, and a pharmacophore model for further rational design was constructed.

中文翻译：

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靶向 TNF/TNFR 信号通路的 Pseudelone C 抗胶质瘤药物构效关系研究


胶质瘤是一种常见的原发性脑肿瘤，具有高度浸润性和侵袭性，常常导致耐药性和复发。因此，迫切需要开发新型治疗剂。 Pseudellone C 是一种新型海洋三吲哚生物碱。对 55 种细胞系的抗增殖活性筛选揭示了其抗中枢神经系统癌症的潜力。设计并合成了总共 42 种 Pseudellone C 衍生物，并使用 CCK-8 测定评估了它们对两种人胶质瘤细胞系（U-87MG 和 LN-229）的抑制活性。 10 种衍生物表现出有效的抗增殖活性，IC 值低于 10 μmol，比 Pseudelone C 强 18 至 39 倍。其中，衍生物表现出良好的血脑屏障通透性。机制研究表明，主要通过 TNF/TNFR 途径激活下游 caspase 3 级联来诱导细胞凋亡。系统分析构效关系，构建药效团模型，为进一步合理设计提供依据。