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.