Dichloroacetophenones targeting at pyruvate dehydrogenase kinase 1 with improved selectivity and antiproliferative activity: Synthesis and structure-activity relationships.
Bioorg Med Chem Lett
; 28(21): 3441-3445, 2018 11 15.
Article
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| MEDLINE
| ID: mdl-30266541
ABSTRACT
Dichloroacetophenone is a pyruvate dehydrogenase kinase 1 (PDK1) inhibitor with suboptimal kinase selectivity. Herein, we report the synthesis and biological evaluation of a series of novel dichloroacetophenones. Structure-activity relationship analyses (SARs) enabled us to identify three potent compounds, namely 54, 55, and 64, which inhibited PDK1 function, activated pyruvate dehydrogenase complex, and reduced the proliferation of NCI-H1975 cells. Mitochondrial bioenergetics assay suggested that 54, 55, and 64 enhanced the oxidative phosphorylation in cancer cells, which might contribute to the observed anti-proliferation effects. Collectively, these results suggested that 54, 55, and 64 could be promising compounds for the development of potent PDK1 inhibitors.
Palabras clave
Texto completo:
1
Bases de datos:
MEDLINE
Asunto principal:
Acetofenonas
/
Proteínas Serina-Treonina Quinasas
/
Inhibidores de Proteínas Quinasas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Asunto de la revista:
BIOQUIMICA
/
QUIMICA
Año:
2018
Tipo del documento:
Article
País de afiliación:
China