Design, concise synthesis and evaluation of novel amide-based combretastatin A-4 analogues as potent tubulin inhibitors.
Bioorg Med Chem Lett
; 108: 129816, 2024 Aug 01.
Article
en En
| MEDLINE
| ID: mdl-38806101
ABSTRACT
As our ongoing work, a novel series of the amide-based CA-4 analogues were successfully designed, synthesized, and explored for their biological evaluation. Among these compounds, 7d and 8a illustrated most potent antiproliferative activity toward A549, HeLa, HCT116, and HT-29 cell lines. Most importantly, these two compounds didn't display noticeable cytotoxic activity on the non-tumoural cell line HEK-293. Further mechanism studies revealed that analogue 8a was identified as a novel tubulin polymerization inhibitor with an IC50 value of 6.90 µM, which is comparable with CA-4. The subsequent investigations unveiled that analogue 8a not only effectively caused cell cycle arrest at the G2/M phase but also induced apoptosis in A549 cells via a concentration-dependent manner. The molecular docking revealed that 8a could occupy well the colchicine-binding site of tubulin. Collectively, these findings indicate that amide-based CA-4 scaffold could be worthy of further evaluation for development of novel tubulin inhibitors with improved safety profile.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Asunto principal:
Estilbenos
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Tubulina (Proteína)
/
Ensayos de Selección de Medicamentos Antitumorales
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Diseño de Fármacos
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Proliferación Celular
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Moduladores de Tubulina
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Simulación del Acoplamiento Molecular
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Amidas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
/
Bioorg. med. chem. lett
/
Bioorganic & medicinal chemistry letters
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2024
Tipo del documento:
Article