Structure-activity relationship study of Pseudellone C as anti-glioma agents by targeting TNF/TNFR signaling pathway.
Eur J Med Chem
; 278: 116799, 2024 Nov 15.
Article
em En
| MEDLINE
| ID: mdl-39213937
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.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Ensaios de Seleção de Medicamentos Antitumorais
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Transdução de Sinais
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Apoptose
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Proliferação de Células
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Glioma
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Antineoplásicos
Limite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China
País de publicação:
França