title: NLNQ-1, a 2-[3-(2-nitro-1-imidazolyl) propylamino]-3-chloro-1,4-naphthoquinone, as a hypoxia-selective cytotoxin and radiosensitizer.
abstract: BACKGROUND
  Compounds bearing two independent redox centers are considered bis-bioreductive agents and usually demonstrate increased hypoxic selectivity with exposure time due to different requirements for reduction of each center. We have synthesized a novel 2-[3-(2-nitro-1-imidazolyl)propylamino]-3-chloro-1,4-naphthoquinone (NLNQ-1), through Michael addition. NLNQ-1, which combines a naphthoquinone (with a relatively high one electron reduction potential) with a 2-nitroimidazole (with a relatively low one electron reduction potential), could perform as a more potent hypoxia-selective cytotoxin and radiosensitizer.
  
  
  METHODS
  NLNQ-1 was evaluated in V79 cells under hypoxic/normoxic conditions, alone or with radiation, by using the clonogenic assay.
  
  
  RESULTS
  Clearly NLNQ-1 was a more potent cytotoxin than the 2-alkylsulfonyloxy-naphthoquinones (VH-compounds), developed previously in our lab, demonstrating hypoxic and aerobic IC50 values at microM rather than mM concentrations. As a radiosensitizer of hypoxic cells, NLNQ-1 was superior to the best bis-nitroimidazolic compound, NNB (which combines a 2-nitroimidazole with a 5-nitroimidazole), demonstrating a C1.6 value of 25.4 microM (ca. 25 fold lower than that of NNB), whereas its in vitro therapeutic index (IC50A/C1.6) ranged from 5.3-13.2.
  
  
  CONCLUSIONS
  NLNQ-1 could be used as a novel scaffold for bis-bioreductive agents that can be properly modified for further optimization of their hypoxia-selective toxicity and radiosensitization properties.
authors.affiliation: Evanston Northwestern Healthcare, Department of Radiation Medicine, IL 60201, USA. m-papadopoulou@northwestern.edu
authors.forename: Maria V
authors.initials: MV
authors.lastname: Papadopoulou
authors.forename: William D
authors.initials: WD
authors.lastname: Bloomer
mesh_terms: D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000528:radiation effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006224:Cricetinae; D007093:Imidazoles / Q000737:chemistry / Q000633:toxicity*; D015394:Molecular Structure; D009285:Naphthoquinones / Q000737:chemistry / Q000633:toxicity*; D011838:Radiation-Sensitizing Agents / Q000737:chemistry / Q000633:toxicity*
chemical_list: C530955:2-(3-(2-nitro-1-imidazolyl)propylamino)-3-chloro-1,4-naphthoquinone; D007093:Imidazoles; D009285:Naphthoquinones; D011838:Radiation-Sensitizing Agents