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The Carcinogenicity of Fluorenylhydroxamic Acids and N-Acetoxy-N-fluorenylacetamides for the Rat as Related to the Reactivity of the Esters toward Nucleophiles¹

Laboratory for Cancer Research, Veterans Administration Hospital, Minneapolis, Minnesota 55417 [Y. Y., H. R. G., R. E. R.], and Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55455 [H. R. G.]

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 mammary 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 > N-hydroxy-3-fluorenylacetamide >> N-hydroxy-4-fluorenylacetamide.

Because of the current concept that arylhydroxamic acids are further activated 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 Sprague-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 > N-acetoxy-3-fluorenylacetamide >> N-acetoxy-4-fluorenylacetamide).

In order to correlate the carcinogenicity 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-fluorenylacetamide, 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 gave with methionine the o and p isomers, 3-methylthio-4-fluorenylacetamide and 1-methylthio-4-fluorenylacetamide. N-Acetoxy-3-fluorenylacetamide did not react with methionine. The isomeric esters exhibited a similar differential reactivity toward transfer RNA from yeast or calf liver. N-Acetoxy-4-fluorenylacetamide yielded minor amounts of an adenosine adduct but, unlike N-acetoxy-2-fluorenylacetamide, failed to react with guanosine. N-Acetoxy-3-fluorenylacetamide did not react with either nucleoside. The weak electrophilicity of N-acetoxy-4-fluorenylacetamide correlated with its marginal carcinogenicity. Because of its lack of reactivity toward nucleophiles, the carcinogen N-acetoxy-3-fluorenylacetamide seemingly contradicted the concept that links the carcinogenicity of N-acetyl-N-arylamines to the electrophilic attack of these compounds on cellular nucleophiles. Two alternate pathways leading to electrophilic reactants are proposed to account for the carcinogenicity of N-acetoxy-3-fluorenylacetamide.

¹ This investigation was supported by Grant CA 02571, NIH. A part of this work was presented at the 65th Annual Meeting of the American Association for Cancer Research, March 27 to 30, 1974, in Houston, Texas.

Received 8/16/74. Accepted 11/ 5/74.