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. Materials and 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 μM 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 C_1.6 value of 25.4 μM (ca. 25 fold lower than that of NNB), whereas its in vitro therapeutic index (IC_50A/C_1.6) ranged from 5.3-13.2. Conclusion: 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.