Structure-activity relationship study of Pseudellone C as anti-glioma agents by targeting TNF/TNFR signaling pathway

  • Eur J Med Chem. 2024 Nov 15:278:116799. doi: 10.1016/j.ejmech.2024.116799.
Xufeng Qin  1 ,  Weifeng Xu  1 ,  Jiangnan Hu  1 ,  Yong Dong  1 ,  Renbo Ding  1 ,  Shuheng Huang  1 ,  Zhendong Zhao  2 ,  Hong Chang  3 ,  Xiaokun Wang  4 ,  Shuai Dong  5
Affiliations
  • 1. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
  • 2. Analytical & Testing Center, Center for Advanced Studies in Precision Instruments, Hainan University, Haikou 570228, China.
  • 3. Hainan Academy of Inspection and Testing, Haikou 570311, China.
  • 4. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China. Electronic address: [email protected].
  • 5. Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China. Electronic address: [email protected].
PMID: 39213937 DOI: 10.1016/j.ejmech.2024.116799
Abstract

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 IC50 values below 10 μmol, which are 18- to 39- fold more potent than Pseudellone C. Among these, derivative 4o demonstrated favorable blood-brain barrier permeability. Mechanistic studies revealed that 4o 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.

Keywords
Anti-glioma; Pseudellone C; Structure-activity relationship; TNF/TNFR pathway.
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