The carcinogenicity of fluorenylhydroxamic acids and N-acetoxy-N-fluorenylacetamides for the rat as related to the reactivity of the esters toward nucleophiles.
In extension of previous work indicating that the carcinogenicity of isomeric fluorenylhydroxamic acids depends on the point of attachment of the nitrogen atom on the fluorene system, the carcinogenicities of N-hydroxy-3-fluorenylacetamide and of N-hydroxy-4-fluorenylacetamide were evaluated in male and female Sprague-Dawley rats by several routes of administration and were compared with the carcinogenicity of N-hydroxy-2-fluorenylacetamide. The earlier observation that N-hydroxy-3-fluorenylacetamide is a specific mamary carcinogen was confirmed. N-Hydroxy-4-fluorenylacetamide was only marginally carcinogenic. Neither isomer gave tumors at the site after i.m. administration of the compounds into the hind leg of the rat. A comparison of the carcinogenicity of the isomers indicated the following order of activity: N-Hydroxy-2-fluorenylacetamide greater than N-hydroxy-3-fluorenylacetamide greater than N-hydroxy-4-fluorenylacetamide. Because of the current concept that arylhydroxamic acids are further acitvated to electrophilic reactants capable of interacting covalently with cellular nucleophiles and because esters of N-hydroxy-2-fluorenylacetamide give rise to an electrophilic reactant, the acetate esters of N-hydroxy-3-fluorenylacetamide and N-hydroxy-4-fluorenylacetamide were prepared and tested for their carcinogenicity in male and female Spaguw-Dawley rats by i.p. and i.m. administration. The order of carcinogenicity of the isomeric esters followed that of the parent hydroxamic acids (N-acetoxy-2-fluorenylacetamide greater than N-acetoxy-3-fluorenylacetamide greater than N-acetoxy-4-fluorenylacetamide). In order to correlate the carcinogeniciyt of the isomeric esters with their reactivity toward nucleophiles, the esters were reacted with methionine, transfer RNA, and the nucleosides, guanosine and adenosine. Under identical conditions, the reactivity of N-acetoxy-2-fluorenylacetamide towards methionine was at least tenfold greater than that of N-acetoxy-4-fluorenylacetamide. In addition to  o-methylthio-2-fluorenylacemide, a new adduct, o-methylsulfoxo-2-fluorenylacetamide, was isolated from the reaction of N-acetoxy-2-fluorenylacetamide with methionine. Reaction of N-acetoxy-4-fluorenylacetamide and 1-methylthio-4-fluorenylacetamide. N-Acetoxy-3-fluorenylacetamide did not react with methionine. Continued.
D000081:Acetamides / Q000633:toxicity; D000085:Acetates; D000230:Adenocarcinoma / Q000139:chemically induced*; D000236:Adenoma / Q000139:chemically induced*; D000241:Adenosine; D000818:Animals; D002250:Carbon Radioisotopes; D002273:Carcinogens; D002467:Cell Nucleus / Q000378:metabolism*; D004563:Electrochemistry; D004952:Esters; D005260:Female; D005449:Fluorenes / Q000633:toxicity*; D006151:Guanosine; D006877:Hydroxamic Acids / Q000031:analogs & derivatives; D007273:Injections, Intramuscular; D007274:Injections, Intraperitoneal; D007536:Isomerism; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000139:chemically induced*; D008715:Methionine; D009584:Nitrogen; D012343:RNA, Transfer; D051381:Rats; D013329:Structure-Activity Relationship
D000081:Acetamides; D000085:Acetates; D002250:Carbon Radioisotopes; D002273:Carcinogens; D004952:Esters; D005449:Fluorenes; D006877:Hydroxamic Acids; D006151:Guanosine; D012343:RNA, Transfer; D008715:Methionine; D000241:Adenosine; D009584:Nitrogen