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Structure-activity relationship study of Pseudellone C as anti-glioma agents by targeting TNF/TNFR signaling pathway
Xufeng Qin1, Weifeng Xu1, Jiangnan Hu1
1Key Laboratory of Tropical Biological Resources of Ministry of Education, School of Pharmaceutical Sciences, Hainan University, Haikou 570228, China.
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.
Insights
Novel marine alkaloid derivatives show potent anti-glioma activity, with one compound demonstrating blood-brain barrier penetration and apoptosis induction. These findings offer new therapeutic avenues for brain cancer treatment.
Area of Science:
- Marine Natural Products Chemistry
- Medicinal Chemistry
- Cancer Biology
Background:
- Glioma is a highly invasive brain tumor with poor drug resistance and high recurrence rates.
- Novel therapeutic strategies are crucial for improving glioma treatment outcomes.
- Pseudellone C, a marine triindole alkaloid, exhibits potential anti-central nervous system (CNS) cancer activity.
Purpose of the Study:
- To design and synthesize novel Pseudellone C derivatives.
- To evaluate the antiproliferative activity of these derivatives against human glioma cell lines.
- To investigate the mechanism of action and structure-activity relationships for optimized drug design.
Main Methods:
- Synthesis of 42 Pseudellone C derivatives.
- Antiproliferative activity assessment using the CCK-8 assay against U-87MG and LN-229 glioma cell lines.
- Blood-brain barrier permeability evaluation and mechanistic studies including apoptosis induction via caspase 3 and TNF/TNFR pathway analysis.
Main Results:
- Ten derivatives displayed significant antiproliferative activity (IC50 < 10 μmol), with potencies 18-39 times greater than Pseudellone C.
- Derivative 4o showed promising blood-brain barrier permeability.
- Derivative 4o induces apoptosis through the TNF/TNFR pathway, activating caspase 3.
Conclusions:
- Novel Pseudellone C derivatives possess potent anti-glioma activity.
- Derivative 4o is a promising candidate for further development due to its efficacy, BBB penetration, and apoptotic mechanism.
- Structure-activity relationship analysis provides a basis for rational drug design against glioma.
