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The Carcinogenicity of the O-Methoxy Derivatives of N-2-Fluorenylacetamide and of Related Compounds in the Rat

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The Carcinogenicity of the O-Methoxy Derivatives of N-2-Fluorenylacetamide and of Related Compounds in the Rat [CANCER RESEARCH 28, 234-244, February 1968] The Carcinogenicity of the o-Methoxy Derivatives of N-2-Fluorenylacetamide and of Related Compounds in the Rat H. R. Gutmann, S. B. Galitski, and W. A. Foley Laboratory ]or Cancer Research, Veterans Administration Hospital, and Department o] Biochemistry, University o] Minnesota, Minneapolis, Minnesota 55417 SUMMARY acetamide by the sequential reactions of deacetylation and oxidation. In order to test the idea that the lack of carcinogenicity of the o-amidofluorenols, N- (1-hydroxy-2-fluorenyl) acetamide and INTRODUCTION N-(3-hydroxy-2-fluorenyl)acetamide, is due to the hydrophilic phenolic hydroxyl group, the methylated derivatives, N-(1- Several model studies from this laboratory have shown that methoxy-2-fluorenyl)acetamide and N-(3-methoxy-2-fluorenyl) the o-quinone imines, 2-imino-l,2-fluorenoquinone and 2-imino- acetamide as well as the hydrochlorides of 1-methoxy-2-fluo- 2,3-fluorenoquinone, which are derived from the carcinogen renamine and 3-methoxy-2-fiuorenamine, were prepared, and N-2-fluorenylacetamide by the sequential enzymatic reactions their carcinogenicity was evaluated in the rat. N-(1-Methoxy- of hydroxylation, deacetylation, and oxidation (6, 10, 12, 27, 2-fluorenyl)acetamide and 1-methoxy-2-fluorenamine hydro- 34, 35), form stable adducts with a variety of proteins (17, 18). chloride, when administered orally to male rats for 5 months, However, the relevance of the binding of these o-quinone imines gave a tumor incidence of 27 and 50%, respectively. Approxi- to chemical carcinogenesis has remained obscure largely be- mately one-half of the lesions produced by either com- cause the o-amidofluorenols, 1-OH-AAF 2 and 3-OH-AAF pound were adenocarcinomas of the small intestine. N-(3- were not carcinogenic by oral and intraperitoneal administration Methoxy-2-fluorenyl) acetamide and 3-methoxy-2-fluorenamine or by bladder implantation (15, 21, 26). It might be argued hydrochloride were inactive. The low-to-moderate carcino- that the lack of activity of these o-amidofluorenols is due to the genicity of N-(1-methoxy-2-fluorenyl)acetamide and of 1- presence of the free phenolic hydroxyl group in the molecule. methoxy-2-fluorenamine hydrochloride contrasted sharply with Because a free hydroxyl group decreases lipid solubility by the high carcinogenicity of the isomeric N-(7-methoxy-2- conferring hydrophilic properties on the molecule (2), the fluorenyl) acetamide and of N-2-fiuorenyl acetamide, which were entry of these compounds into the cell may be retarded. In run for comparison under identical conditions. N-(7-Methoxy- addition, the free hydroxyl group may facilitate the formation 2-fluorenyl)acetamide appeared to be specifically active toward of water-soluble conjugates and, thus, the elimination of the the mammary gland. compounds from the cell. These factors would tend to counter- The intracellular removal of the O-methyl group of N-(1- act the attainment of the minimum intracellular concentration methoxy-2-fluorenyl)acetamide was demonstrated by means of which may be required for biologic activity. Observations con- N-(1-methoxy-2-fluorenyl)acetamide labeled with 14C in the cerning the enhancement of the carcinogenic activity of a num- methyl group. The formation of N-(1-hydroxy-2-fluorenyl)- ber of hydroxylated compounds by methylation (5, 22, 23) acetamide, indicated by the radioactive tracer experiments, was appear to support this line of reasoning. Once the methylated confirmed by the isolation of N-(1-hydroxy-2-fluorenyl)acet- compound has penetrated the cell membrane, the methyl group amide from the urine of rats dosed with N-(1-methoxy-2- would presumably be removed by intracellular demethylases fiuorenyl)acetamide. The metabolic O-demethylation of N-(1- and the active compound (or its precursor) would be released. methoxy-2-fluorenyl)acetamide was compatible with the view Based on these considerations, the methylated derivatives of 1- that N-(1-hydroxy-2-fluorenyl)acetamide, when liberated in OH-AAF and of 3-OH-AAF, 1-MeO-AAF and 3-MeO-AAF, situ, may be weakly carcinogenic. However, the striking dif- respectively, were prepared (28). The present report deals with ferences in the carcinogenicities, as well as in the sites of action the evaluation of the carcinogenicity of these compounds in the of the o-methoxy compounds and of N-2-fluorenyl acetamide, make it exceedingly improbable that the carcinogenic activity 2The following abbreviations are used: 1-OH-AAF, N-(1-hy- of N-2-fluorenylacetamide is mediated through N-(1-hydroxy- droxy-2-fluorenyl)acetamide; 3-OH-AAF, N-(3-hydroxy-2-fluo- renyl) acetamide ; 5-OH-AAF, N-(5-hydroxy-2-fluorenyl)acetamide ; 2-fluorenyl)acetamide or through the o-quinone imine, 2-imino- 7-OH-AAF, N-(7-hydroxy-2-fluorenyl)acetamide; 1-MeO-AAF, 1,2-fluorenoquinone, resulting from N-(1-hydroxy-2-fluorenyl) N-(1-methoxy-2-fluorenyl) acetamide ; 1-MeO-14C-AAF, N- (1- methoxy-14C-2-fluorenyl) acetamide; 3-MeO-AAF, N-(3-methoxy- 1 This investigation was supported by USPHS Research Grant 2-fluorenyl)acetamide; 7-MeO-AAF, N-(7-methoxy-2-fluorenyl)- CA-02571 from the National Cancer Institute. acetamide; 1-MeO-AF-HCI, 1-methoxy-2-fluorenamine hydrochlo- Received June 28, 1967; accepted October 5, 1967. ride; 3-MeO-AF-HC1, 3-methoxy-2-fluorenamine hydrochloride. 234 CANCER RESEARCH VOL. 28 Downloaded from cancerres.aacrjournals.org on October 1, 2021. © 1968 American Association for Cancer Research. Carcinogenicity of Fluorenylacetamide Derivatives rat as compared to the activity of N-2-fluorenylacetamide and N-2-Fluorenylacetamide. N-2-Fluorenylacetamide, m.p. 196- of 7-MeO-AAF, a position isomer of the o-methoxy derivatives 198~ was obtained by acetylating 2-fluorenamine, m.p. 128- of N-2-fluorenylaeetamide. In addition, the o-demethylation in 130~ (19), in the usual manner (30). rive of 1-MeO-AAF which displayed some carcinogenic activity Preparation of 1-MeO-14C-AAF. To a solution of 1-OH-AAF has been investigated. (100 mg, 0.42 mmole), m.p. 210-212~ (25), in 10 ml of 0.5 N potassium hydroxide was added 2.0 mmoles of dimethyl-14C sulfate (specific radioactivity = 1.25 me/mmole) (New England MATERIALS AND METHODS Nuclear Corp., 575 Albany Street, Boston, Mass.). After the Preparation of Compounds. 1-MeO-AAF, m.p. 148-150~ reaction mixture had been stirred for 1 hour, 2.1 mmoles of A~1o~ 2S8 m~ (e, 24,600), and 3-McO-AFF, m.p. 169-171~ unlabeled dimethylsulfate were added, and stirring was con- II~OX tinued for one additional hour. The reaction mixture was cen- were prepared as described previously (28). trifuged and the precipitate was washed twice with 0.5 N po- 1-MeO-AF'HC1. 1-Methoxy-2-nitrofluorene (0.241 gin, 1 tassium hydroxide. The residue was dissolved in 95% ethanol, mmole), m.p. 100-102~ (28), in ethanol (25 ml) and con- and 20 mg of unlabeled 1-MeO-AAF and a small amount of centrated hydrochloric acid (1 ml), was hydrogenated at room Norite A were added. The mixture was heated briefly on the temperature and atmospheric pressure with palladium black steam bath and was then filtered through a layer of eelite. (0.075 gm) (Nutritional Bioehemicals Corp., Cleveland 28, Water was added to the filtrate to incipient turbidity. After Ohio) as a catalyst. After hydrogen uptake had ceased, the 12 hours at 4~ the 1-MeO-14C-AAF was collected and dried reaction mixture was filtered and the solvent was evaporated over calcium chloride. There was obtained 27.0 mg of 1-MeO -~4 at reduced pressure. The resulting solid was dissolved in hot C-AAF, m.p. 150-151~ (with softening at 138-140~ The distilled water and filtered through eelite into concentrated hy- labeled compound was chromatographed on silica gel GF2s~ drochloric acid (3 ml). The amine hydrochloride which crystal- with chloroform:methanol (97:3) as a solvent. The radioactiv- lized on cooling in an ice-bath was purified by two reerystalliza- ity profile, obtained by plotting the radioactivity against the tions from dilute hydrochloric acid. 1-MeO-AF" HCI (0.120 distance from the origin, showed a single radioactive peak which gin, 48% yield) decomposed over a range from 205 to 217~ coincided with the fluorescence-quenching spot (tlF = 0.46) Calculated for C14H14NOCl: C, 67.87; H, 5.69; N, 5.65. seen on exposure of the ehromatogram to ultraviolet light Found: C, 67.89 ; H, 5.68; N, 5.59. (2537 A), Authentic 1-MeO-AAF, run concurrently, had the The compound was ehromatographed on Whatman No. 1 paper same II F value. Radioassay of 1-MeO-14C-AAF before and after by the descending technic with 2.4 N hydrochloric acid as the thin-layer chromatography on silica gel GF2~ ~ gave practically ......... 9~ gave a Mllgte orange spot ~ = 0.28) when the t~p identical values for the specific radioactivity (1.07 • 106 developed chromatogram was sprayed with a 1% solution of p-dimethylaminobenzaldehyde in N hydrochloric acid. 1-MeO- 0.9 AF-HC1 was converted to 1-methoxy-2-fluorenamine, m.p. 108.5-109~ (28), in 78% yield by pouring the amine hydro- 0.8 chloride dissolved in 95% ethanol into an aqueous sodium bi- carbonate solution. The precipitate was collected, washed with water, and dried over calcium chloride. 0.7- 3-MeO-AF'HC1. 3-Methoxy-2-nitrofluorene (1.5 gm, 0.67 mmole), m.p. 180-182~ (28), was dissolved in a mixture of 0.& glacial acetic acid (150 ml), ethyl acetate (100 ml), and con- O centrated hydrochloric acid (8 ml). The mixture was hydrogen- t-. ,~ 0.5 ated at room temperature and atmospheric pressure with pal- ladium black (0.45 gm) as a catalyst.
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