Design, synthesis and biological evaluation of novel para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones as human PARP-1 inhibitors.
- Author:
Hai-Ping YAO
;
Zhi-Xiang ZHU
;
Ming JI
;
Xiao-Guang CHEN
;
Bai-Ling XU
- Publication Type:Journal Article
- MeSH:
Antineoplastic Agents;
chemical synthesis;
chemistry;
pharmacology;
Drug Design;
Enzyme Inhibitors;
chemical synthesis;
chemistry;
pharmacology;
Molecular Docking Simulation;
Molecular Structure;
Poly (ADP-Ribose) Polymerase-1;
Poly(ADP-ribose) Polymerases;
Quinazolinones;
chemical synthesis;
chemistry;
pharmacology;
Structure-Activity Relationship
- From:
Acta Pharmaceutica Sinica
2014;49(4):497-503
- CountryChina
- Language:Chinese
-
Abstract:
Poly(ADP-ribose) polymerase-1 (PARP-1) has emerged as a promising anticancer drug target due to its key role in the DNA repair process. It can polymerize ADP-ribose units on its substrate proteins which are involved in the regulation of DNA repair. In this work, a novel series of para-substituted 1-benzyl-quinazoline-2, 4 (1H, 3H)-diones was designed and synthesized, and the inhibitory activities against PARP-1 of compounds 7a-7e, 8a-8f, 9a-9c and 10a-10c were evaluated. Of all the tested compounds, nine compounds displayed inhibitory activities with IC50 values ranging from 4.6 to 39.2 micromol x L(-1). In order to predict the binding modes of the potent molecules, molecular docking was performed using CDOCKER algorithm, and that will facilitate to further develop more potent PARP-1 inhibitors with a quinazolinedione scaffold.
