N-nitroso-N-2-fluorenylacetamide: a new direct-acting mutagen and teratogen.
Reaction of N-2-fluorenylacetamide (2-FAA, CAS No. 53-96-3) with nitrous fume (N2O3) in glacial acetic acid at 0 degree C yields N-nitroso-N-2-fluorenylacetamide (N-NO-2-FAA), 3-nitro-N-2-fluorenylacetamide, N-nitroso-3-nitro-N-2-fluorenylacetamide and other compounds. N-NO-2-FAA is the major product (80%) and fairly stable at low temperature (-20 degrees C), but extremely labile at ambient temperature. The chemical structure of N-NO-2-FAA is characterized by spectrometric analysis of its naphthol coupling derivatives. This new compound is highly mutagenic to Salmonella typhimurium TA97, TA98, TA100 and TA1538 and requires no microsomal metabolic activation. The mutagenicity of N-NO-2-FAA in TA98 is higher than that of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG, CAS No. 70-25-7) and N-acetoxy-N-2-fluorenylacetamide (N-AcO-2-FAA). The teratogenic potential of N-NO-2-FAA was studied with white Leghorn chick embryos given a single dose of 1-100 micrograms/egg on day 6 of incubation. A high incidence of flaccid paralysis of the legs and a low incidence of feather, claw and bill malformations were found in the treated group; no such malformed embryos were found in the control group. The teratogenicity of N-NO-2-FAA was found to be weaker than that of MNNG, but comparable to that of N-methyl-N-nitrosourea (CAS No. 684-93-5). N-NO-2-FAA is a strong electrophile and reacts readily with histidine, lysine, cysteine, glutathione, tryptophan, adenosine, cytidine at neutral pH. In contrast to N-AcO-2-FAA, N-NO-2-FAA does not react significantly with guanosine and thymidine. It seems that N-NO-2-FAA is a strong direct-acting mutagen and probably a new prototype of synthetic carcinogen.
D015073:2-Acetylaminofluorene / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000633:toxicity; D000014:Abnormalities, Drug-Induced; D000241:Adenosine; D000596:Amino Acids; D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D002642:Chick Embryo; D002851:Chromatography, High Pressure Liquid; D003562:Cytidine; D004249:DNA Damage / Q000187:drug effects; D005978:Glutathione; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008769:Methylnitronitrosoguanidine / Q000633:toxicity; D008770:Methylnitrosourea / Q000633:toxicity; D009154:Mutation; D009603:Nitroso Compounds / Q000494:pharmacology / Q000633:toxicity*; D009705:Nucleosides; D012486:Salmonella typhimurium / Q000187:drug effects; D013055:Spectrophotometry, Infrared
D000596:Amino Acids; D009603:Nitroso Compounds; D009705:Nucleosides; C057157:N-nitroso-N(2)-fluorenylacetamide; D008769:Methylnitronitrosoguanidine; D003562:Cytidine; D008770:Methylnitrosourea; D015073:2-Acetylaminofluorene; D005978:Glutathione; D000241:Adenosine