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热带海洋学报

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海洋生物碱 Pseudellone C 的结构简化及其脑胶质瘤细胞毒活性研究胶质瘤活性研究

董泳1, 胡江南1, 王琨2, 姚敏1, 乔焱博1, 朱成晨1, 董帅1
  

  1. 1. 热带生物资源教育部重点实验室, 海南大学药学院, 海南 海口 570228;

    2. 牡丹江医科大学附属红旗医院, 黑龙江 牡丹江 157009



  • 收稿日期:2026-02-10 修回日期:2026-03-19 接受日期:2026-03-23
  • 通讯作者: 董帅
  • 基金资助:

    海南省自然科学基金(823MS031)

Structural Simplification and Anti-glioma Cytotoxic Activity of the Marine Alkaloid Pseudellone CSea Fungus-Derived Alkaloid Pseudellone C and Its Anti-Glioma Activity

DONG Yong1, HU Jiangnan1, WANG Kun2, YAO Min1, QIAO Yanbo1, ZHU Chengchen1, DONG Shuai1   

  1. 1. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China;

    2. Hongqi Hospital Affiliated to Mudanjiang Medical University, Mudanjiang 157009, China



  • Received:2026-02-10 Revised:2026-03-19 Accepted:2026-03-23
  • Supported by:
    Natural Science Foundation of Hainan Province(823MS031)

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摘要： 南海海洋微生物是发现结构新颖次级代谢产物的重要宝库。Pseudellone C是一种源于南海软珊瑚内生真菌次级代谢产物, 前期研究发现其衍生物具有抗脑胶质瘤的潜力, 但仍存在分子量大及成药性差等瓶颈。为深入探究其抗肿瘤活性的核心药效团, 优化其结构保持活性并提升成药性, 本研究开展了基于天然产物骨架简化的药物设计研究。共合成了10个新型3,3'-二吲哚基丙酸衍生物(2a~2j)。该系列化合物以吲哚或6-溴吲哚为起始原料, 经路易斯酸催化的双分子傅-克烷基化反应构建核心骨架, 随后通过酰胺缩合引入多样化侧链。采用CCK-8(cell counting kit-8)法和划痕实验评价目标化合物对人脑胶质瘤细胞株U-87 MG和LN-229的体外抗增殖活性及迁移能力的影响。结果表明, 简化后的衍生物活性普遍优于天然产物pseudellone C。其中, 引入2-(3-吲哚基)乙基侧链的化合物2e表现出最优活性, 对U-87 MG和LN-229的半抑制率浓度(half maximal inhibitory concentration, IC50)值分别为9.0 ± 0.7µmol·L-1和5.7 ± 0.7µmol·L-1, 且呈剂量依赖性地显著抑制细胞迁移。构效关系分析表明, 在侧链引入富电子芳香环以及在母核6-位进行卤代修饰可显著增强抗肿瘤活性。本研究初步证实了对天然产物pseudellone C开展结构简化可获得活性更优的衍生物, 成功筛选出具有较高抗脑胶质瘤活性及抗迁移潜力的先导化合物2e, 为后续海洋来源抗脑胶质瘤先导化合物的优化奠定基础。

关键词: 南海天然产物, Pseudellone C, 吲哚类生物碱, 结构简化, 脑胶质瘤

Abstract: Marine microorganisms from the South China Sea represent a prolific source of structurally novel secondary metabolites. Pseudellone C, a trisindole alkaloid derived from a soft coral-associated fungus in this region, possesses promising anti-glioma activity but is compromised by its high molecular weight and suboptimal druggability. To elucidate its core pharmacophore and enhance its drug-like properties, a drug design strategy based on scaffold simplification was employed. Ten novel 3,3'-bis(indolyl)propanoic acid derivatives (2a~2j) were designed and synthesized; the core skeleton was constructed via a Lewis acid-catalyzed bimolecular Friedel-Crafts alkylation, followed by amide condensation to introduce diverse side chains. Biological evaluation using cell counting kit-8 (CCK-8) and wound healing assays demonstrated that the simplified analogues generally exhibited superior anti-proliferative potency compared to the natural parent compound. Notably, compound 2e, incorporating a 2-(3-indolyl)ethyl moiety, displayed the most potent activity against U-87 MG and LN-229 glioma cells with half maximal inhibitory concentration (IC50) values of 9.0 ± 0.7µmol·L-1 and 5.7 ± 0.7µmol·L-1, respectively. Furthermore, 2e significantly inhibited glioma cell migration in a dose-dependent manner. Structure-activity relationship analysis revealed that the introduction of electron-rich aromatic moieties to the side chain, combined with C-6 halogenation of the indole core, significantly enhanced antitumor efficacy. This study establishes that scaffold simplification of the natural product pseudellone C effectively generates derivatives with improved pharmacological profiles. Through systematic evaluation, compound 2e was identified as a promising lead, exhibiting potent anti-glioma efficacy and significant inhibition of cell migration. These results provide a compelling rationale for the continued optimization of marine-inspired scaffolds in the pursuit of advanced anti-glioblastoma therapeutics.

Key words: South China sea natural products, Pseudellone C, Indole alkaloids, Structural simplification, Glioma.