Synthesis and evaluation of 3-(phenylethynyl)-1,1'-biphenyl-2-carboxylate derivatives as new HIF-1 inhibitors.
Bioorg Chem
; 116: 105298, 2021 11.
Article
em En
| MEDLINE
| ID: mdl-34454298
ABSTRACT
Selaginellins are a type of rare natural products from the genus Selaginella with unusual alkynyl phenol skeletons and extensive biological activities. Previous structural simplification of these natural compounds afforded a series of diaryl acetylene derivatives with hypoxia-inducible factor 1 (HIF-1) inhibitory activity. In this study, we synthesized thirty compounds by stepwise optimization using methyl 3-(4-methoxylphenyl ethynyl)-[4'-methoxyl-1,1'-biphenyl]-2-carboxylate (1a) as a lead compound and evaluated their HIF-1 inhibitory activity by dual luciferase reporter assay. Among them, compound 9i displayed the most potent HIF-1 inhibitory activity (IC50 = 1.5 ± 0.03 µM) with relatively low cytotoxicity. Under hypoxia, compound 9i showed no effect on the accumulation of HIF-1α protein in western blot analysis, but could down-regulate the expression of VEGF mRNA, the downstream target gene of HIF-1 pathway. Cell-based activity assay demonstrated that compound 9i could inhibit the hypoxia-induced migration, invasion and proliferation of HeLa cells at the concentrations of 1 ~ 5 µM. In mouse breast cancer xenograft model, compound 9i exhibited obvious tumor growth inhibition and very low toxicity at a dose of 15 mg/kg. The results suggested that compound 9i would be a potential antitumor agent via HIF-1 pathway inhibition.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Compostos de Bifenilo
/
Ácidos Carboxílicos
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Subunidade alfa do Fator 1 Induzível por Hipóxia
/
Antineoplásicos
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
China