Synthesis of novel 2-nitroimidazole-tethered tricyclic quinolines, bearing a second heteroatom, and their in vitro evaluation as hypoxia-selective cytotoxins and radiosensitizers

• Published in: Bioorganic & medicinal chemistry letters 2004-03, Vol.14 (6), p.1523-1525
• Main Authors: Papadopoulou, Maria V., Rosenzweig, Howard S., Bloomer, William D.
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Hypoxia - drug effects; Cell Hypoxia - physiology; Cricetinae; Drug Evaluation, Preclinical - methods; General aspects; Heterocyclic Compounds - chemical synthesis; Heterocyclic Compounds - toxicity; Intercalating Agents - chemical synthesis; Intercalating Agents - toxicity; Medical sciences; Nitroimidazoles - chemical synthesis; Nitroimidazoles - toxicity; Pharmacology. Drug treatments; Quinolines - chemical synthesis; Quinolines - toxicity; Radiation therapy and radiosensitizing agent; Radiation-Sensitizing Agents - chemical synthesis; Radiation-Sensitizing Agents - toxicity; Treatment with physical agents; Treatment. General aspects; Tumors
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2003.12.102

Two novel nitroimidazole-based bioreductive compounds, 10-[3-(2-nitroimidazolyl)-propylamino]-3,4-dihydro-1 H-thiopyrano[4,3- b]quinoline hydrochloride ( 8a) and 10-[3-(2-nitroimidazolyl)propylamino]-2-methyl-1,2,3,4-tetrahydro-benzo[ b]-1,6-naphthyridine hydrochloride ( 8b) have been synthesized and evaluated in V79 cells as hypoxia-selective cytotoxins and radiosensitizers that target DNA through weak intercalation. Both compounds were relatively good radiosensitizers (C 1.6 values of 40.0±0.8 and 59.0±0.4 μM for 8a and 8b, respectively) but neither of the compounds was superior to 2 which does not carry a second heteroatom in the DNA-intercalating chromophore. Two novel weak DNA-intercalating bioreductive compounds have been synthesized and evaluated in vitro as hypoxia-selective cytotoxins and radiosensitizers.