Design and Synthesis of Novel Quinone Inhibitors Targeted to the Redox Function of Apurinic/Apyrimidinic Endonuclease 1/Redox Enhancing Factor-1 (Ape1/Ref-1)

The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Apel/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Apel can therefore serve as a therapeutic target in either a DNA repair or transcriptional context. Inhibitors of the redox function can be used as either therapeutics or novel tools for separating the two functions for in vitro study. Presently there exist only a few compounds that have been reported to inhibit Apel redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Apel. Benzoquinone and naphthoquinone analogues of the Apel-inhibitor E3330 were designed and synthesized to explore structural effects on redox function and inhibition of cell growth. Most of the naphthoquinones were low micromolar inhibitors of Apel redox activity, and the most potent analogues inhibited tumor cell growth with IC50 values in the 10-20 mu M range.