Novel Benzamide Derivatives: Synthesis and Bioactivity as Potent PARP ‐1 Inhibitors

The poly(ADP‐ribose) polymerases (PARPs) are located in the nuclei of cells and involved in DNA damage repair. PARP inhibitors have been used to target BRCA1/2‐defective cells that experience increases in DNA single‐strand breaks (SSBs). In the presence of PAPR inhibitors, these SSBs are converted into irreparable and toxic double‐strand breaks (DSBs) during replication, eventually leading to cell death due to genome instability caused by the impaired homologous‐mediated repair system. We designed and synthesized several novel benzamide derivatives based on the previously reported PARP‐1‐inhibitory activities of benzoxazole and benzamide moieties. Next, we used an in vitro assay to quantify their PARP‐1 inhibitory activity and evaluate their potential as possible anti‐cancer therapeutics. Compound 28d contains a hydroxamate group and showed a significant inhibitory capacity (IC50 value of 3.2 μM; 2.8‐ and 4.2‐fold decrease in SNU‐251 and MDA‐MB‐231 cells, respectively, compared with the DMSO‐treated controls). Based on these results, we suggest that we have identified a novel hydroxybenzamide derivative of a benzamide moiety which is known as a key pharmacophore in existing PARP inhibitors.