Structure-activity relationship of hexameihyl-melamine derivatives

Twenty derivatives of hexa-methylmelamine (HMM) from AT2071 to 2080 and from AT2093 to 2102. substituted by car-boxymethyl hydrazine or acetic ether groups for the methyl groups of HMM were studicd by measurement of released formaldehyde catalyzed by microsomal enzymes, antitumor test against rat W206 carcinosarcoma in vivo. in vitro/in vivo, microbiological, and spermatogonium tests. The amount of released formaldehyde after enzymatic activation were 0-22.4% of that of HMM. There was a correlation between the number of N-methyl groups and the amount of released formaldehyde. HMM and AT2071 showed antitumor activities in vivo. The W256 tumor cells, cultivated with drugs activated by liver microsome beforehand, were transplanted to the subcutaneous tissue of rats and the anti-tumor effect (in vitro/in vivo) was judged by the growth of the tumor in rats. The results were expressed by inhibition rate of tumor growth in comparison with controls. HMM, AT2071, 2072 and 2096 possessed antitumor activity only after microsomal activation. The amount of released formaldehyde from these 4 compounds containing 2 dimethyl nitrogen groups were considerably higher than those from other compounds in this series. The only exception was AT2095 which contained 5 methyl groups released a double amount of formaldehyde as that of AT2071, but possessed only marginal antitumor effect. This suggested that the number of N-methyl groups and the amount of reieased formaldehyde were not parailel sheerly with their antitumor activities. Two or more dimethyl nitrogen were necessary for the antitumor activity. Carboxymethylhydrazine groups reduced the biological effects of N-methyl groups of the melamine, whereas melamine ring reduced also the effects of carboxymethylhydrazine groups. All compounds showed negative results in spermatogonium test and microbiological assay, suggesting that they might not be antimetabolites and could not prevent DNA synthesis in the cells. The antitumor studies against W256 carcinosarcoma in vitro/in vivo suggest that the mechanism of their action may be due to the interaction of the released active methyl group with the biologic macromolecules in the cells.