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The Carcinogenicities of Derivatives of Fluorene and Biphenyl: Fluoro Derivatives as Probes for Active Sites in 2-Acetylaminofluorene^*

Elizabeth C. Miller, T. Lloyd Fletcher, Alfredo Margreth and James A. Miller

( McArdle Memorial Laboratory for Cancer Research, Medical School, University of Wisconsin, Madison, Wisconsin; and Chemistry Research Laboratory, Department of Surgery, Medical School, University of Washington, Seattle, Washington)

The carcinogenic activities of the 1-, 3-, 4-, 5-, 6-, and 8-monofluoro derivatives of 2-acetylaminofluorene (AAF) were compared with the activity of AAF in male and female rats. Each of these monofluoro derivatives and the 7-fluoro derivative reported previously was found to possess approximately the same carcinogenic activity as AAF in two or more of the four tissues in which AAF commonly produces tumors in the Holtzman rat. This result suggests that none of the aromatic ring-positions of AAF is a site of covalent bond formation necessary for carcinogenesis by this amide. Thus, the carcinogenicities of the monofluoro derivatives of AAF are consistent with the recent finding that N-hydroxylation of AAF is directly involved in carcinogenesis with this compound.

Comparative carcinogenicities were also determined in the rat for a series of other fluorene derivatives related to AAF and for several compounds related to 4-acetylaminobiphenyl. 2-Trifluoroacetylaminofluorene, 2-trifluoroacetylaminofluoren-9-one, 2-formylaminofluorene, 2,7-dinitrofluorene, 2,5-bis(acetylamino)fluorene, and 3'-fluoro-4-acetylaminobiphenyl induced moderate to high incidences of tumors at one or more sites. Introduction of a 3-methyl group into 4-acetylaminobiphenyl reduced its activity for the mammary gland, but enhanced its activity toward the ear duct gland. 3-Fluoro-4-acetylaminobiphenyl was strongly carcinogenic for the mammary glands of both female and male rats. 2,5-Dinitrofluorene, 2-dimethylamino-3-nitrofluorene, 2-acetylamino-9-(p-fluorophenylimino)fluorene, p,p'-methylenediacetanilide, 4'-methyl-4-acetylaminobiphenyl, 2-acetylthiofluorene, 2-maleimidofluorene, and 2-methylthiofluorene had little or no activity in any tissue under the conditions employed.

Syntheses of the following new compounds are described: 3- and 3'-fluoro-4-acetylbiphenyl and their oximes, 3- and 3'-fluoro-4-acetylaminobiphenyl (synthesized by F. Chubb and R. B. Sandin), and 2-formylaminofluorene.

^* This investigation was supported by Grants C355 and C1744 of the National Institutes of Health, United States Public Health Service; a grant from the Jane Coffin Childs Memorial Fund for Medical Research; and by the Alexander and Margaret Stewart Trust Fund.

Present address: Institute of General Pathology, University of Padua.

Received 5/14/62.