SYNTHESIS AND BIOLOGICAL EVALUATION OF 3-CARBAMOYLBENZOIC DERIVATIVES AS INHIBITORS OF HUMAN APURINIC/APYRIMIDINICENDONUCLEASE 1 (APE1)

Apurinic/apyrimidinic endonuclease 1 (APE1) is a multifaceted protein with an essential role in the base excision repair (BER) pathway. Its implication in tumor development, progression, and resistance has been confirmed in multiple cancers, making it a viable target for intensive investigation. APE1 also shows a protective effect in several cancer models to a variety of DNA damaging agents. A B Figure. Synthesized compounds with descriptive hydrophobic, negative ionizable, and linker moieties. A) Synthesized 3-carbamoylbenzoic acid derivatives. B) Subsequently synthesized 6-benzylcarbamoylpyridine, 8-hydroxyqunoline-2-carboxamide, and N-benzylbenzamide derivatives. Previous studies led to the discovery of a series of compounds based on APE1 three-dimensional pharmacophore model.1 Further small molecules containing a 3-carbamoylbenzoic acid scaffold have been successively synthesized in order to increase activity and cytotoxicity (Figure).2 Several of the new compounds were shown to inhibit the catalytic endonuclease function of APE1 with potencies in the low-micromolar range. Among these promising series of compounds, derivatives bearing a 3-benzylcarbamoyl-2-methoxybenzoic acid structure, resulted as the most active and selective inhibitors of APE1, showing IC50 values < 20 m. Any activity against HIV1-IN, a similar enzyme having an endonuclease activity, was not detected for the compounds at the highest concentrations tested, thus proving a high degree of selectivity. The 3-benzylcarbamoyl-2- methoxybenzoic acid moiety, common to all active derivatives, represents a lead scaffold to be further developed with the aim to find more potent and selective analogs. References 1Zawahir Z.; Dayam R.; Deng J.; Pereira C.; Neamati N., Pharmacophore Guided Discovery of Small- Molecule Human Apurinic/Apyrimidinic Endonuclease 1 Inhibitors, J Med Chem 2009, 52 (1), 20–32. 2Aiello F.; Shabaik Y.; Esqueda A.; Sanchez T. W.; Grande F.; Garofalo A.; Neamati N., Design and Synthesis of 3-Carbamoylbenzoic Derivatives as Inhibitors of Human Apurinic/Apyrimidinic Endonuclease 1 (APE1), CHEMMEDCHEM, 2012, 7, 1825-1839.