Synthesis and anticancer evaluation of 6-azacyclonol-2,4,6-trimethylpyridin-3-ol derivatives: M3 muscarinic acetylcholine receptor-mediated anticancer activity of a cyclohexyl derivative in androgen-refractory prostate cancer.
Bioorg Chem
; 110: 104805, 2021 05.
Article
en En
| MEDLINE
| ID: mdl-33725508
We recently reported 2,4,5-trimethylpyridin-3-ol with C(6)-azacyclonol, whose code name is BJ-1207, showing a promising anticancer activity by inhibiting NOX-derived ROS in A549 human lung cancer cells. The present study was focused on structural modification of the azacyclonol moiety of BJ-1207 to find a compound with better anticancer activity. Ten new compounds (3A-3J) were prepared and evaluated their inhibitory actions against proliferation of eighteen cancer cell lines as a primary screening. Among the ten derivatives of BJ-1207, the effects of compounds 3A and 3J on DU145 and PC-3, androgen-refractory cancer cell lines (ARPC), were greater than the parent compound, and compound 3A showed better activity than 3J. Antitumor activity of compound 3A was also observed in DU145-xenografted chorioallantoic membrane (CAM) tumor model. In addition, the ligand-based target prediction and molecular docking study using DeepZema® server showed compound 3A was a ligand to M3 muscarinic acetylcholine receptor (M3R) which is overexpressed in ARPC. Carbachol, a muscarinic receptor agonist, concentration dependently increased proliferation of DU145 in the absence of serum, and it also activated NADPH oxidase (NOX). The carbachol-induced proliferation and NOX activity was significantly blocked by compounds 3A in a concentration-dependent manner. This finding might become a new milestone in the development of pyridinol-based anti-cancer agents against ARPC.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Piperidinas
/
Neoplasias de la Próstata
/
Piridinas
/
Receptor Muscarínico M3
/
Descubrimiento de Drogas
/
Antineoplásicos
Tipo de estudio:
Prognostic_studies
Límite:
Humans
/
Male
Idioma:
En
Revista:
Bioorg Chem
Año:
2021
Tipo del documento:
Article
Pais de publicación:
Estados Unidos