State Key Laboratory of Natural Medicines, Department of TCMs Pharmaceuticals, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, People's Republic of China.
State Key Laboratory of Bioelectronics, Jiangsu Laboratory for Biomaterials and Devices, Southeast University, Nanjing 210009, People's Republic of China.
J Med Chem. 2021 Aug 26;64(16):12089-12108. doi: 10.1021/acs.jmedchem.1c00735. Epub 2021 Aug 18.
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.
聚（ADP-核糖）聚合酶-1（PARP-1）是发现化疗增敏剂和抗癌药物的潜在靶点。山柰酚（amentoflavone）被报道为选择性 PARP-1 抑制剂。在这里，对 进行了结构修饰和修剪，分别得到了一系列 的衍生物（）和芹菜素-哌嗪/哌啶杂合体（，，，和）。在这些化合物中，表现出很强的 PARP-1 抑制作用（IC = 14.7 nM），并且对 PARP-1 具有很高的选择性，相对于 PARP-2 的选择性为 61.2 倍。分子动力学模拟和细胞热转移测定显示，直接与 PARP-1 结构结合。在 和 研究中，通过 PARP-1 抑制，对 A549 细胞显示出很强的化疗增敏作用，对 SK-OV-3 细胞显示出选择性细胞毒性作用。还表现出良好的 ADME 特征、药代动力学参数和理想的安全边际。这些发现表明，可能作为化疗增敏剂和（BRCA-1）缺陷型癌症治疗的先导化合物。
