Journal of Tropical Oceanography

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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)

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.