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 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.

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.

• Authors: Maria V Papadopoulou, William D Bloomer
• Journal: In vivo (Athens, Greece) (In Vivo) 2008 May-Jun Vol. 22 Issue 3 Pg. 285-8 ISSN: 0258-851X [Print] Greece
• PMID: 18610737 (Publication Type: Journal Article)

Chemical References

• 2-(3-(2-nitro-1-imidazolyl)propylamino)-3-chloro-1,4-naphthoquinone
• Imidazoles
• Naphthoquinones
• Radiation-Sensitizing Agents

Topics

• Animals
• Cell Hypoxia (drug effects, radiation effects)
• Cell Line
• Cell Survival (drug effects, radiation effects)
• Cricetinae
• Imidazoles (chemistry, toxicity)
• Molecular Structure
• Naphthoquinones (chemistry, toxicity)
• Radiation-Sensitizing Agents (chemistry, toxicity)