Nitroaryl compounds as potential fluorescent probes for hypoxia. II. Identification and properties of reductive metabolites.
Nitroakridin 3582 (NA) and a nitronaphthalimide (DM113), which fluoresce only upon reduction, have been studied by HPLC. V79-379A cells incubated with NA under 20% or 2% O2 and N2 gave increasing amounts of the fluorescent amine with an hypoxic:oxic differential of 160. Measurement of the uptake of NA showed that it was concentrated within the cell by over 1000-fold. Studies in 3 different cell lines of reduction under hypoxia showed a 7-fold range in amine production. DM113 yields more than one fluorescent product, which show different absorption and fluorescence spectra. Chemical reduction of NA or DM113 using a variety of methods gave, depending on conditions, amine and/or (what was presumed to be) hydroxylamine; the latter was non-fluorescent. In vivo, NA is toxic at greater than 0.19 mumol g-1. At this dose much of the drug is found in the liver and kidneys. Plasma levels at 30 minutes are only 2 microM while tumor concentrations are 10 microM compared to 600 microM in the liver. However, the half life is greater than 1 hr and amine was detectable in these tumors.
D000585:Aminacrine / Q000031:analogs & derivatives / Q000378:metabolism / Q000633:toxicity; D000609:Aminoacridines; D000818:Animals; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D005456:Fluorescent Dyes; D008297:Male; D051379:Mice; D009374:Neoplasms, Experimental / Q000473:pathology; D010084:Oxidation-Reduction; D010100:Oxygen
D000609:Aminoacridines; D005456:Fluorescent Dyes; C039997:nitroacridine 3582; D000585:Aminacrine; C042599:DM 119; D010100:Oxygen