Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 64, Issue 16, Pages 12089-12108Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.1c00735
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Funding
- National Natural Science Foundation of China [81973206, 82073804, U1801287]
- China Postdoctoral Science Foundation [2019M662006, 2019TQ0357]
- Funding of Double First-rate Discipline Innovation Team [CPU2018PZQ17, CPU2018PZQ18, CPU2018GF05]
- Major National Science and Technology Projects of the Chinese Thirteen Five-year Plan [2017ZX09309024]
- Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program [2017BT01Y036]
- Research and Innovation Project for College Graduates of Jiangsu Province [KYCX17_0694]
- Jiangsu Province Graduate Student Training Innovation Project [KYLX16_1208]
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This study discovered a series of compounds with potential PARP-1 inhibitory activity through structural modifications and trimming of amentoflavone (AMF). Among these compounds, 15l showed strong PARP-1 inhibitory effects with high selectivity. These compounds may serve as lead compounds for chemosensitizers and therapy for (BRCA-1)-deficient cancer.
Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone (AMF) is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of AMF have led to a series of AMF derivatives (9a-h) and apigenin-piperazine/piperidine hybrids (14a-p, 15a-p, 17a-h, and 19a-f), respectively. Among these compounds, 15l exhibited a potent PARP-1 inhibitory effect (IC50 = 14.7 nM) and possessed high selectivity to PARP-1 over PARP-2 (61.2-fold). Molecular dynamics simulation and the cellular thermal shift assay revealed that 15l directly bound to the PARP-1 structure. In in vitro and in vivo studies, 15l showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. 15l center dot 2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l center dot 2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.
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