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

Poly (ADP-ribose) polymerase-1 (PARP-1) is a potential target for the discovery of chemosensitizers and anticancer drugs. Amentoflavone () is reported to be a selective PARP-1 inhibitor. Here, structural modifications and trimming of have led to a series of derivatives () and apigenin-piperazine/piperidine hybrids (, , , and ), respectively. Among these compounds, exhibited a potent PARP-1 inhibitory effect (IC = 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 directly bound to the PARP-1 structure. In and studies, showed a potent chemotherapy sensitizing effect against A549 cells and a selective cytotoxic effect toward SK-OV-3 cells through PARP-1 inhibition. also displayed good ADME characteristics, pharmacokinetic parameters, and a desirable safety margin. These findings demonstrated that may serve as a lead compound for chemosensitizers and the (BRCA-1)-deficient cancer therapy.