The Relative Carcinogenic Activity of Six Isomeric Aminoazotoluenes

IT has been suggested from studies of the action of inhibitors of S-metabolism on tumour induction by carcinogenic hydrocarbons that S-metabolism and the process of carcinogenesis are closely linked (Crabtree, 1947). This association is emphasized when the properties of azo-carcinogens are considered. The products of their metabolism have been shown to inhibit the activities of urease (Potter, 1942) and succinoxidase (Elson and Hoch-Ligeti, 1944), two enzymes dependent upon intact SH-groups for their proper functioning. Kensler, Dexter and Rhoads (1942) studied the relative inhibitory action of a series of " split-products " on a standard diphospho-pyridine-nucleotide system, and sought to correlate this activity with the carcinogenic power of the parent azo-compound. Suggestive parallelisms were found, but a clear-cut relationship did not emerge. Much of this work has been based on the conception (experimentally verified for p-dimethylaminoazobenzene by Stevenson, Dobriner and Rhoads (1942), and for azo-benzene by Elson and Warren (1944)) that an azo-carcinogen is initially metabolized by the process of reductive fission with the liberation of an amine and a diamine, and that the latter is the effective carcinogen by virtue of its capacity to interfere with normal enzymic. activities. It is not clear why the diamine moiety alone should have been conceived as having special significance for the process of cancer induction. A survey of the azo-compounds so far tested for carcinogenic activity makes it evident that in some cases the amine moiety of the reduced molecule plays a significant role in determining potency, e.g. on comparing p-dimethylaminoazobenzene with its p'-methyl derivative, the introduction of the p'-methyl group causes a change from a very strong to a very weak carcinogen. The present work was undertaken to probe this problem further. Isomeric aminoazotoluenes were chosen as suitable for a study of the relative contributions made by the amines and diamines which would arise from their reduction. The well-known carcinogen 4'-amino-2 3'-azotoluene (o: o) and the non-carcinogen 2'-amino-4: 5'-azotoluene (p: p) served as bases of reference, and their behaviour was compared with that of the hybrid compounds o: p and p: o. Two other isomers-i : m and p: m-were also tested to provide further comparative data. Note on abbreviatioms used.-All the isomeric aminoazotoluenes are prepared by coupling diazotized o-, m-, or p-toluidine with o-, m-, or p-toluidine, and the abbreviations reflect their molecular structure, e.g. p: m signifies that diazotized p-toluidine is coupled with m-toluidine, forming 4'-amino-4: 2'-azotoluene, and so on.