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The Carcinogenicity of the o-Methoxy Derivatives of N-2-Fluorenylacetamide and of Related Compounds in the Rat¹

Laboratory for Cancer Research, Veterans Administration Hospital, and Department of Biochemistry, University of Minnesota, Minneapolis, Minnesota 55417

In order to test the idea that the lack of carcinogenicity of the o-amidofluorenols, N-(1-hydroxy-2-fluorenyl)acetamide and N-(3-hydroxy-2-fluorenyl)acetamide, is due to the hydrophilic phenolic hydroxyl group, the methylated derivatives, N-(1-methoxy-2-fluorenyl) acetamide and N-(3-methoxy-2-fluorenyl)acetamide as well as the hydrochlorides of 1-methoxy-2-fluorenamine and 3-methoxy-2-fluorenamine, were prepared, and their carcinogenicity was evaluated in the rat. N-(1-Methoxy-2-fluorenyl)acetamide and 1-methoxy-2-fluorenamine hydrochloride, when administered orally to male rats for 5 months, gave a tumor incidence of 27 and 50%, respectively. Approximately one-half of the lesions produced by either compound were adenocarcinomas of the small intestine. N-(3-Methoxy-2-fluorenyl)acetamide and 3-methoxy-2-fluorenamine hydrochloride were inactive. The low-to-moderate carcinogenicity of N-(1-methoxy-2-fluorenyl)acetamide and of 1-methoxy-2-fluorenamine hydrochloride contrasted sharply with the high carcinogenicity of the isomeric N-(7-methoxy-2-fluorenyl)acetamide and of N-2-fluorenyl acetamide, which were run for comparison under identical conditions. N-(7-Methoxy-2-fluorenyl) acetamide appeared to be specifically active toward the mammary gland.

The intracellular removal of the O-methyl group of N-(1-methoxy-2-fluorenyl)acetamide was demonstrated by means of N-(1-methoxy-2-fluorenyl)acetamide labeled with ¹⁴C in the methyl group. The formation of N-(1-hydroxy-2-fluorenyl)acetamide, indicated by the radioactive tracer experiments, was confirmed by the isolation of N-(1-hydroxy-2-fluorenyl)acetamide from the urine of rats dosed with N-(1-methoxy-2-fluorenyl)acetamide. The metabolic O-demethylation of N-(1-methoxy-2-fluorenyl)acetamide was compatible with the view that N-(1-hydroxy-2-fluorenyl)acetamide, when liberated in situ, may be weakly carcinogenic. However, the striking differences in the carcinogenicities, as well as in the sites of action of the o-methoxy compounds and of N-2-fluorenyl acetamide, make it exceedingly improbable that the carcinogenic activity of N-2-fluorenylacetamide is mediated through N-(1-hydroxy-2-fluorenyl)acetamide or through the o-quinone imine, 2-imino-1,2-fluorenoquinone, resulting from N-(1-hydroxy-2-fluorenyl)acetamide by the sequential reactions of deacetylation and oxidation.

¹ This investigation was supported by USPHS Research Grant CA-02571 from the National Cancer Institute.

Received 6/28/67. Accepted 10/ 5/67.