American Chemical Society
jm1c00735_si_004.csv (5.51 kB)
Download file

Discovery of Novel Apigenin–Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase‑1 (PARP-1) Inhibitors for the Treatment of Cancer

Download (5.51 kB)
posted on 2021-08-18, 07:30 authored by Huan Long, Xiaolong Hu, Baolin Wang, Quan Wang, Rong Wang, Shumeng Liu, Fei Xiong, Zhenzhou Jiang, Xiao-Qi Zhang, Wen-Cai Ye, Hao Wang
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·2HCl also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that 15l·2HCl may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.