Identification of novel PARP-1 inhibitors: Drug design, synthesis and biological evaluation.
A series of AG014699 derivatives containing a novel scaffold of 2,3-dihydro-1H-[1,2]diazepino[4,5,6-cd]indole-1,4(6H)-dione were synthesized and evaluated for their inhibitory activities toward PARP-1 enzyme and two cell lines, MCF-7 cells and the BRCA1-deficient MDA-MB-436 cells. Our results demonstrated that of all AG014699 derivatives synthesized in this work, compounds 6 and 7 showed strong PARP-1 inhibitory activity (IC50=3.5 nM and 2.4 nM, respectively), only four and three times less potent than AG014699. Compound 6 also had significantly cell inhibitory activity against both MCF-7 cells (CC50=25.8 μM) and the BRCA1-deficient MDA-MB-436 cells (CC50=5.4 μM), nearly as good as AG014699, indicating that it can be a promising compound for further evaluation.
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Zhouling
Z
Xie
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Youli
Y
Zhou
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 21009, China.
Wei
W
Zhao
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
He
H
Jiao
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China.
Yu
Y
Chen
State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing 21009, China.
Yong
Y
Yang
Jiangsu Key Laboratory of Drug Design and Optimization, China Pharmaceutical University, Nanjing 21009, China. Electronic address: zhiyuli@cpu.edu.cn.
Zhiyu
Z
Li
D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D000071137:Poly (ADP-Ribose) Polymerase-1; D000067856:Poly(ADP-ribose) Polymerase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011065:Poly(ADP-ribose) Polymerases / Q000378:metabolism*; D013329:Structure-Activity Relationship
D007211:Indoles; D000067856:Poly(ADP-ribose) Polymerase Inhibitors; C531549:rucaparib; C499320:PARP1 protein, human; D000071137:Poly (ADP-Ribose) Polymerase-1; D011065:Poly(ADP-ribose) Polymerases
BRCA1/2-deficient; DNA damage; Inhibitor; Molecular docking; Poly ADP-ribose polymerase-1 (PARP-1)