title: Design and synthesis of novel quinone inhibitors targeted to the redox function of apurinic/apyrimidinic endonuclease 1/redox enhancing factor-1 (Ape1/ref-1).
abstract: The multifunctional enzyme apurinic endonuclease 1/redox enhancing factor 1 (Ape1/ref-1) maintains genetic fidelity through the repair of apurinic sites and regulates transcription through redox-dependent activation of transcription factors. Ape1 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 Ape1 redox activity; here we describe a series of quinones that exhibit micromolar inhibition of the redox function of Ape1. Benzoquinone and naphthoquinone analogues of the Ape1-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 Ape1 redox activity, and the most potent analogues inhibited tumor cell growth with IC(50) values in the 10-20 microM range.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, Cancer Center, Purdue University, West Lafayette, Indiana 47907, USA.
authors.forename: Rodney L
authors.initials: RL
authors.lastname: Nyland
authors.forename: Meihua
authors.initials: M
authors.lastname: Luo
authors.forename: Mark R
authors.initials: MR
authors.lastname: Kelley
authors.forename: Richard F
authors.initials: RF
authors.lastname: Borch
mesh_terms: D016227:Benzoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000037:antagonists & inhibitors*; D015195:Drug Design; D024202:Electrophoretic Mobility Shift Assay; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D005260:Female; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008689:Methacrylates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009285:Naphthoquinones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000473:pathology; D010084:Oxidation-Reduction; D011422:Propionates / Q000737:chemistry*
chemical_list: C569501:3-(3-chloro-1,4-naphthoquinon-2-yl)-2-methylpropenoic acid; D016227:Benzoquinones; D004791:Enzyme Inhibitors; D008689:Methacrylates; D009285:Naphthoquinones; D011422:Propionates; C075569:E 3330; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase