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.