Cytotoxic Agents: I, Methylolamides With Tumour Inhibitory Activity, and Related Inactive Compounds

natural or synthetic fibres these substances modify the mechanical properties of the fabrics in various ways, conferring, for example, increased wet strength upon paper and crease-resisting properties upon cotton or woollen textiles.Their usefulness in this direction is probably associated, as described by our colleague Mr. J.G.Evans (1949), with their poly-alkylating function and with the formation of cross-linkages between adjacent polymer fibres.The possible biological significance of the polyalkylating and cross-linking potentialities of the sulphur and nitrogen mustards had been brought to our attention by Professor A. Haddow and his group (private communication, and Haddow, Kon, and Ross, 1948), more particularly in connexion with the aryl nitrogen mustards then under investigation by them; this observation gave additional stimulus to the hypothetical ideas then being developed.The dependence of the characteristic toxicological properties of the nitrogen mustards upon the presence in the molecule of at least two 8-chloroethyl groups emerges from early work with these agents and had been noted, for example, by Karnovsky, Burchenal, Ormsbee, Cornman, and Rhoads (1947); similarly Elmore, Gulland, Jordan, and Taylor (1948) found evidence for cross-linkage in one of the products isolated from the reaction between desoxyribonucleic acid and mustard gas, and suggested that their investigation provided a chemical parallel to previous cytological observations with the latter.While the methylolamides were under investigation we learnt also from Professor Haddow of the hypothesis, since elaborated and published (Goldacre, Loveless, and Ross, 1949;Loveless and Revell, 1949), that the specific cytotoxic action of the nitrogen mustards might be due to the formation of linkages between cell nuclear components.At this stage it appeared that the methylolamides found active as tumour inhibitors were to be regarded essentially as " mustard " analogues rather than as acting like urethane, and this conception appeared to be substantiated by a more detailed study of the biological action of trimethylolmelamine.Moreover, it seemed probable that cross-linkage was in some way involved in the mechanism of action.Certain results, however, made it clear that the capacity to function as a simple cross-linking agent was not alone sufficient as a criterion of potential tumour inhibi- tory activity.Meanwhile the results obtained with trimethylolmelamine had already directed our attention to other chemical types having similar technological applica- tions, namely, bis-epoxides and certain compounds containing two or three ethylenimine residues (Rose, Hendry, and Walpole, 1950), and with the discovery of tumour inhibitory activity among these substances a further chemical condition for biological activity became apparent.The results obtained with these alternative types, however, form the subject of a later communication in this series.The present paper is concerned with the initial group of substances capable of reacting with amino groups and with the methylolamides which immediately followed them.Finally, in addition to the many compounds mentioned above, there were also included in these investigations several substances selected in connexion with another hypothesis relating to the action of urethane.Although it has never been demon- strated in vitro, the possibility exists that urethane, like the related isocyanate ion, might, in vivo, give a trimeric condensation product of the 1: 3: 5-triazine type or, more specifically, triethyl cyanurate.This compound, being tri-functional, might then produce cross-linking effects.It was therefore synthesized and examined together with the trimethyl ester and the corresponding acid halide, cyanuric chloride.