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Novel Benzamide Derivatives: Synthesis and Bioactivity as Potent PARP ‐1 Inhibitors
Author(s) -
Ryu Hwani,
Ahn Jiyeon,
Choi Hyun Kyung
Publication year - 2017
Publication title -
bulletin of the korean chemical society
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.237
H-Index - 59
ISSN - 1229-5949
DOI - 10.1002/bkcs.11207
Subject(s) - benzamide , poly adp ribose polymerase , pharmacophore , chemistry , polymerase , dna damage , moiety , dna repair , dna , in vitro , stereochemistry , biochemistry
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 ( IC 50 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.