Comparative electrophilicity, mutagenicity, DNA repair induction activity, and carcinogenicity of some N- and O-acyl derivatives of N-hydroxy-2-aminoflourene.
N-Myristoyloxy-N-acetyl-2-aminofluorene, N-acetoxy-N-myristoyl-2-aminofluorene, N-myristoyloxy-N-myristoyl-2-aminofluorene, and N-hydroxy-N-myristoyl-2-aminofluorene each yielded a high incidence of sarcomas in male rats within 5 to 7 months after s.c. injection of 64 micronmoles in divided doses. N-Acetoxy-N-acetyl-2-aminofluorene and N-hydroxy-2-acetylaminofluorene, although potent carcinogens at the s.c. site, were less active than the above derivatives with a myristoyl substituent. N-Sulfonoxy-N-acety--2-aminofluorene (purity larger than or equal to 70%) had little or no carcinogenic activity when administered in large amounts by s.c. injection to rats. The low incidence of tumors could have resulted from N-hydroxy-2-acetylaminofluorene or other decompostion products of the N-sulfonozy derivative. Each of the N-acetoxy and N-myristoyloxy derivatives of N-acetyl-2-aminofluorene and of N-myristoyl-2-aminofluorene showed electrophilic activity toward methionine; N-acetoxy-N-acetyl-2-aminofluorene was the most reactive and N-myristoyloxy-N-myristoyl-2-aminofluorine was the least reactive. Each of these esters also induced unscheduled tritiated thymidine incorportation in nondividing cultured human fibroblasts and thus appeared to induce lesions in DNA that lead to repair synthesis. EACH OF THE N-acetoxy derivatives was highly mutagenic for Salmonella typhimurium strains TA98 and TA1538 without tissue activation; neither N-myristoyloxy derivative was mutagenic under these conditions. While there was a qualitative correspondence between several of the above activities of these 2-aminofluorene derivatives, the quantitative differences and the lack of detectable mutagenicity of the 2N-myristoyloxy derivatives for S. typhimurium indicate the need for multiple short-term tests in the qualitative prediction of potential carcinogenic activity.
D000818:Animals; D002273:Carcinogens; D055598:Chemical Phenomena; D002621:Chemistry; D004260:DNA Repair; D005449:Fluorenes / Q000494:pharmacology*; D006881:Hydroxyacetylaminofluorene / Q000031:analogs & derivatives / Q000494:pharmacology*; D008297:Male; D008715:Methionine; D009153:Mutagens; D051381:Rats; D012486:Salmonella typhimurium / Q000187:drug effects; D012513:Sarcoma, Experimental / Q000139:chemically induced*
D002273:Carcinogens; D005449:Fluorenes; D009153:Mutagens; D006881:Hydroxyacetylaminofluorene; D008715:Methionine