Synthesis of novel 2-nitroimidazole-tethered tricyclic quinolines, bearing a second heteroatom, and their in vitro evaluation as hypoxia-selective cytotoxins and radiosensitizers.
Two novel nitroimidazole-based bioreductive compounds, 10-[3-(2-nitroimidazolyl)-propylamino]-3,4-dihydro-1H-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 microM 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.
Evanston Northwestern Healthcare, Deptartment of Radiation Medicine, Evanston, IL 60201, USA. papadopoulou@northwestern.edu
Maria V
MV
Papadopoulou
Howard S
HS
Rosenzweig
William D
WD
Bloomer
D000818:Animals; D015687:Cell Hypoxia / Q000187:drug effects / Q000502:physiology; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006571:Heterocyclic Compounds / Q000138:chemical synthesis* / Q000633:toxicity; D007364:Intercalating Agents / Q000138:chemical synthesis / Q000633:toxicity; D009593:Nitroimidazoles / Q000138:chemical synthesis* / Q000633:toxicity; D011804:Quinolines / Q000138:chemical synthesis* / Q000633:toxicity; D011838:Radiation-Sensitizing Agents / Q000138:chemical synthesis* / Q000633:toxicity
D006571:Heterocyclic Compounds; D007364:Intercalating Agents; D009593:Nitroimidazoles; D011804:Quinolines; D011838:Radiation-Sensitizing Agents