Design, Synthesis and Biological Evaluation of Novel Anticancer Agents Based on APE1 Pharmacophore Model

Human apurinic/apyrimidinic endonuclease 1 (APE1) is an important enzyme in the base excision repair(BER) pathway that is essential for the repair of abasic sites in the genome. Evidence for APE1 as anattractive therapeutic target in anticancer drug development has been demonstrated by studies that linkoverexpression of APE1 in many cancers to resistance to radio- and chemo-therapy. APE1 also shows aprotective effect in several cancer cell models to a variety of DNA damaging agents.The pharmacophore perception is a popular technique in drug design to identify small-molecule inhibitorswith diverse chemical scaffolds. It has been successfully used to discover several classes of clinically relevantsmall-molecule targeting a number of pathways, including DNA repair.1 Previous studies led to the discoveryof a series of compounds based on APE1 three-dimensional (3D) pharmacophore model. In an effort to bettercharacterize the mode of action of these compounds, we planned a synthetic pathway for the preparation of a newclass of 3-carbamoylbenzoic acid derivatives potentially active against APE1. Synthesized compounds displayed agood APE1 inhibitory activity in preliminary in vitro assays. The most active derivative 1 (Fig 1B) inhibited APE1model with an IC50 = 4.8 μM. Structure-activity analysis of the tested compounds could represents a firstinformative structural platform for a further rational optimization of this class of small-molecules to theidentification of more potent and selective inhibitors of APE1.1 Zahrah Zawahir, Raveendra Dayam, Jinxia Deng, Cherelene Pereira and Nouri Neamati, PharmacophoreGuided Discovery of Small-Molecule Human Apurinic/Apyrimidinic Endonuclease 1 Inhibitors J Med Chem2009, 52 (1), pp 20–32