Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer.
Discovery of Novel Apigenin-Piperazine Hybrids as Potent and Selective Poly (ADP-Ribose) Polymerase-1 (PARP-1) Inhibitors for the Treatment of Cancer.
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DOI：
10.1021/acs.jmedchem.1c00735
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发表时间：
2021-08
影响因子：
7.3
通讯作者：
H. Long;Xiao-long Hu;Bao-Lin Wang;Quan Wang;Rong Wang;Shumeng Liu;F. Xiong;Zhenzhou Jiang
中科院分区：
文献类型：
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作者：
H. Long;Xiao-long Hu;Bao-Lin Wang;Quan Wang;Rong Wang;Shumeng Liu;F. Xiong;Zhenzhou Jiang
聚（ADP-核糖）聚合酶-1 (PARP-1) 是发现化学增敏剂和抗癌药物的潜在靶标。据报道，Amentoflavone (AMF) 是一种选择性 PARP-1 抑制剂。在这里，AMF 的结构修饰和修剪分别产生了一系列 AMF 衍生物 (9a-h) 和芹菜素-哌嗪/哌啶杂化物 (14a-p、15a-p、17a-h 和 19a-f)。在这些化合物中，15l表现出有效的PARP-1抑制作用（IC50 = 14.7 nM），并且对PARP-1的选择性高于对PARP-2的选择性（61.2倍）。分子动力学模拟和细胞热位移测定表明15l直接与PARP-1结构结合。在体外和体内研究中，15l 对 A549 细胞显示出有效的化疗增敏作用，并通过 PARP-1 抑制对 SK-OV-3 细胞具有选择性细胞毒作用。 15l·2HCl 还表现出良好的 ADME 特性、药代动力学参数和理想的安全裕度。这些发现表明 15l·2HCl 可作为化学增敏剂和 (BRCA-1) 缺陷型癌症治疗的先导化合物。
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.