Design, synthesis and structure-activity relationship optimization of phenanthridine derivatives as new Wnt/ß-catenin signalling pathway agonists.
Bioorg Chem
; 84: 285-294, 2019 03.
Article
en En
| MEDLINE
| ID: mdl-30529846
ABSTRACT
Phenanthridine derivativeHLY78 has previously been identified as the first Wnt/ß-catenin signalling pathway agonist that targets the DAX domain of axin. However, due to the relatively weak activation on the Wnt/ß-catenin signalling pathway, HLY78 is insufficient for further pharmacological study. Herein, the structural optimization of HLY78 and analyses of the structure-activity relationships (SARs) of HLY78-derived phenanthridine derivatives as agonists of the Wnt/ß-catenin signalling pathway are presented. In this work, 36 derivatives were designed and synthesized with some derivatives exhibiting stronger Wnt activity than the activity of HLY78. In particular, one of them, 8-((1,3-dimethy-pyrazol-5-yl)methoxy)-5-ethyl-4-methyl-5,6-dihydro-phenanthridin-9-ol, exhibited strong Wnt active activity and is 10 times more potent than HLY78. The following SAR analysis suggests that a pyrazole group, especially at the C-8 position, is important for Wnt activation; a methyl group at the C-4position seems to be more beneficial for Wnt activation than ethyl; and oxidation of the C-6 position reduces the Wnt activation.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Fenantridinas
/
Diseño de Fármacos
/
Proteínas Wnt
/
Beta Catenina
Tipo de estudio:
Prognostic_studies
Límite:
Humans
Idioma:
En
Revista:
Bioorg Chem
Año:
2019
Tipo del documento:
Article
País de afiliación:
China