Synthesis and structure-activity relationship study of novel 3-diethoxyphosphorylfuroquinoline-4,9-diones with potent antitumor efficacy.
Eur J Med Chem
; 219: 113429, 2021 Jul 05.
Article
en En
| MEDLINE
| ID: mdl-33852973
Herein we report an efficient synthesis of a series of regioisomeric N,O-syn and N,O-anti 3-diethoxyphosphorylfuroquinoline-4,9-diones combining furoquinoline-5,8-dione skeleton, present in several highly cytotoxic compounds, with diethoxyphosphoryl moiety. The cytotoxic activity of the obtained analogs was tested against two human cancer cell lines: promyelocytic leukemia HL-60 and breast cancer adenocarcinoma MCF-7 and for comparison on human umbilical vein endothelial cells HUVEC and mammary gland/breast MCF-10 A cells. Several diethoxyphosphorylfuroquinoline-4,9-diones proved to be highly cytotoxic for cancer cells with IC50 values even below 0.1 µM. Interestingly, N,O-syn 3-diethoxyphosphorylfuroquinoline-4,9-diones were 3- to 7-fold more active against HL-60 cells than the respective N,O-anti regioisomers. The most promising analogs 9c and 9i, with the highest cancer/healthy cells cytotoxicity ratio, were further evaluated to establish their mode of action. In HL-60 cells these analogs enhanced intracellular ROS generation and NAD(P)H:quinone oxidoreductase 1 (NQO1) depletion which led to the cell cycle arrest in the S-phase, reduced cell proliferation, DNA damage and apoptosis.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Quinolonas
/
Antineoplásicos
Límite:
Humans
Idioma:
En
Revista:
Eur J Med Chem
Año:
2021
Tipo del documento:
Article
País de afiliación:
Polonia
Pais de publicación:
Francia