The carcinogenic activities of certain analogues of 2-acetyl-aminofluorene in the rat.

a carcinogen originally discovered by Wilson, DeEds, and Cox (28), has been shown by these and many other investigators to be a highly active carcinogen that attacks nu merous sites in the rat and mouse. In addition, the parent hydrocarbon, fluorene, and several of its other derivatives have been tested for carcinogenic activity in the rat. Fluorene and its oxidation product, fluorenone, are inactive (30). While 2-ni trofluorene is only weakly carcinogenic (19) its reduction product, 2-aminofluorene, is highly ac tive although somewhat less so than 2-acetylami nofluorene (2, 12, 19, 30). The activity of the latter compound is not greatly changed upon conversion to the diacetyl derivative (19). 7-Hydroxy-2-ace tylaminofluorene, a metabolite of 2-acetylamino fluorene in the rat (3), has but little activity in this species (13)'. Similarly, the miscellaneous de rivatives xanthone and 2-chlorofluorene are non carcinogenic (30). The objective of the study reported here was to determine if the-CH2-bridge in 92-acetylamino fluorene is essential to its carcinogenic activity in the rat. Three analogues were tested in which the bridges consisted of either-S-as in 3-acetylamino dibenzothiophene,-@-as in 3-acetylaminodibenzo 0 thiophene-5-oxide, or-0-as in 3-acetylaminodi benzofuran (see Table I for structures). The ac tivity of 4-dimethylaminobiphenyl is also de scribed. This compound, a derivative of 2-amino fluorene in which the bridge is absent, was original 1 The control rats in this study were killed at 500 days while the rats fed 7-hydroxy-2-acetylaminofluorene were killed at 700 days. ly tested as an analogue of the hepatic carcinogen 4-dimethylaminoazobenzene. METHODS Preparation of compoun&†" @2-Aminofluorene, pre pared from fluorene2 as described by Kuhn (14), was acetylated by dissolving it in excess hot acetic anhydride containing 1 to 2 per cent of redistilled pyridine. The 2-acetylaminofluorene was precipitated by the addition of @2 to 3 volumes of water, filtered, washed, and dried. It was then dissolved in hot ethanol, refluxed twice with 10 per cent of its weight of charcoal, and finally crystal lized by the addition of water. The final yield, calculated from fluorene, was 50 per cent. The recrystallized product was nearly white and melted at 190°†" 191° C. 3-Acetylaminodibenzothiophene, m.p. 198°†" 199° C., and 3-acetylaminodibenzothiophene-5-oxide, m.p. 275°†" 276° C., were synthesized from dibenzothiophene as de scribed previously (5). 3-Aminodibenzofuran, prepared by the method of Gilman and Avakian (9), was acety lated by heating for 1 hour on a water bath a benzene solution of the amine with …