Carcinogenic activity of some heterocyclic analogs of p-dimethylaminoazobenzene. II. Effects of methyl groups in the pyridine ring.

The first paper of this series (1) reported the results of tests of the carcinogenic activity of cer tam analogs of p-dimethylaminoazobenzene (DAB) in which a pyridine ring or a thiazole ring replaced one of the benzene rings of DAB. Due to the presence of the hetero atom or atoms, position isomers are possible in the heterocyclic analogs, and some of these isomers were synthesized and tested. The wide variations in activity exhibited by isomers in the pyridine and pyridine-1-oxide series suggested the synthesis and testing of certain ad ditional analogs, some of which are reported here. In the pyridine series, pyridine-2-azo-p-dimethyl aniline (Ps) and pyridine-3-azo-p-dimethylaniline (PS) produced no tumors in the test animals dur ing the period of observation, whereas pyridine-4azo-p-dimethylaniline (P4) was effective in induc ing tumors. In the pyridine-1-oxide series, the van ation in activity was much more striking, since pyridine-1-oxide-@-azo-p-dimethylaniline (POe) was found to be inactive, whereas pynidine-1oxide-4-azo-p-dimethylaniline (P04) was found to be extremely active. One of the interesting findings of J. A. Miller and co-workers (4) in their extensive studies on the carcinogenicity of derivatives of DAB was that the introduction of substituents into the unsubstituted benzene ring produced varying effects depending upon the position of the substituent relative to the azo linkage. The effect of a given substituent may be to increase or decrease the activity relative to the parent compound, but, as a general rule, the activity of the derivatives is in the order m'> o'> p'. For example, where the substituent is the