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.