Isoquinolinone–Naphthoquinone Hybrids as Potent PARP‑1 Inhibitors Induce Apoptosis in Glioma via DNA Damage and ROS Generation

We report a series of fused isoquinolinone–naphthoquinone
hybrid molecules as PARP-1 inhibitors. Our efforts led to the identification
of compounds 5c and 5d, which display potent
PARP-1 inhibition in enzymatic assays with IC50 values
of 2.4 and 4.8 nM and demonstrated consistent antiproliferative activity
in C6 glioma cells, with IC50 values of 1.34
± 0.02 and 1.35 ± 0.009 μM, respectively. Notably,
both molecules showed similar efficacy in U87MG glioma cells with
IC50 values of 1.28 ± 0.03 and 1.33 ±
0.01 μM, respectively. 5c and 5d induced
apoptosis in both glioma cells by promoting PARP cleavage, triggering
DNA damage, and increasing ROS. Furthermore, they effectively inhibited
cell migration and significantly reduced colony formation in both
glioma cells. Thus, the results identify the hybrid isoquinolinone–naphthoquinone
scaffolds (5c and 5d) as a promising lead
hit for PARP-1 inhibition in glioma, offering a new scaffold for future
drug development.

本研究报道了一系列稠合异喹啉酮-萘醌杂合分子作为聚腺苷二磷酸核糖聚合酶-1（PARP-1）抑制剂。本课题组通过筛选鉴定得到化合物5c与5d，二者在酶学测定中展现出强效的PARP-1抑制活性，半数抑制浓度（IC50）分别为2.4 nM与4.8 nM；同时在C6胶质瘤细胞中表现出稳定的抗增殖活性，IC50值分别为1.34 ± 0.02 μM与1.35 ± 0.009 μM。值得注意的是，两种化合物在U87MG胶质瘤细胞中亦展现出相近的抗肿瘤活性，IC50值分别为1.28 ± 0.03 μM与1.33 ± 0.01 μM。5c与5d可通过促进PARP剪切、诱发DNA损伤以及提升活性氧（ROS）水平，诱导两种胶质瘤细胞发生细胞凋亡。此外，二者可有效抑制细胞迁移，并显著降低两种胶质瘤细胞的集落形成能力。综上，本研究证实稠合异喹啉酮-萘醌杂合骨架（5c与5d）是一类极具潜力的PARP-1抑制先导化合物，可为胶质瘤治疗领域的后续药物开发提供全新的分子骨架。