QSAR prediction, synthesis, anticancer evaluation, and mechanistic investigations of novel sophoridine derivatives as topoisomerase I inhibitors.
Fitoterapia
; 175: 105921, 2024 Jun.
Article
em En
| MEDLINE
| ID: mdl-38561052
ABSTRACT
Sophoridine, which is derived from the Leguminous plant Sophora alopecuroides L., has certain pharmacological activity as a new anticancer drug. Herein, a series of novel N-substituted sophoridine derivatives was designed, synthesized and evaluated with anticancer activity. Through QSAR prediction models, it was discovered that the introduction of a benzene ring as a main pharmacophore and reintroduced into a benzene in para position on the phenyl ring in the novel sophoridine derivatives improved the anticancer activity effectively. In vitro, 28 novel compounds were evaluated for anticancer activity against four human tumor cell lines (A549, CNE-2, HepG-2, and HEC-1-B). In particular, Compound 26 exhibited remarkable inhibitory effects, with an IC50 value of 15.6 µM against HepG-2 cells, surpassing cis-Dichlorodiamineplatinum (II). Molecular docking studies verified that the derivatives exhibit stronger binding affinity with DNA topoisomerase I compared to sophoridine. In addition, 26 demonstrated significant inhibition of DNA Topoisomerase I and could arrest cells in G0/G1 phase. This study provides valuable insights into the design and synthesis of N-substituted sophoridine derivatives with anticancer activity.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Quinolizinas
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Relação Quantitativa Estrutura-Atividade
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Sophora
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Alcaloides
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Inibidores da Topoisomerase I
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Simulação de Acoplamento Molecular
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Matrinas
Limite:
Humans
Idioma:
En
Revista:
Fitoterapia
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China