Mutagenic Alkylating Agents 295 



In spite of widely differing constitution the active agents all 

 share the property of reacting under physiological conditions 

 with nucleophilic (i.e. electron-rich) centres; and that their 

 biological activity is derived from the ability to change some 

 vital molecules in the cell by alkylation seems certain. 



There are very many points at which these agents can react 

 in the cell, and the most important are amino (or imino) 

 groups in their uncharged state and anions such as the 

 ionized carboxyl groups in proteins and the phosphate groups 

 of nucleic acid. Ionized — SH groups (i.e. — S~) react so 

 readily with these alkylating agents that even at pH 7 all the 

 available — SH groups are readily alkylated although less 

 than 0-1 per cent of them are present in the reactive — S~ 

 form at any one time. 



In spite of the great diversity of possible reactions it 



is possible to eliminate a number of these by considering 



compounds which are inactive although they have some of 



these reactions in common. Hendry, Rose and Walpole 



(1951) examined a large number of compounds which were 



known to react with amino groups by alkylation (such as the 



alkyl halides), by acylation or in other ways, but which could 



not esterify anions. Although they were not tested by these 



authors for mutagenic properties none showed cytotoxic 



effects on tumours which are such a characteristic feature of 



the radiomimetic alkylating agents. Similar negative results 



have been obtained more recently by Haddow (unpublished) 



with a number of bifunctional thiol esters of the type 



R'S-CORCO-S-R' which combine with amine groups under 



biological conditions. We studied in some detail one of the 



amine reactors used by Hendry, Rose and Walpole (1951), 



triacrylformal, 



^ N— COCH-CHg 



CH2 CH2 



I I 



CH2=CHC0N NC0CH=CH2 



CH, 



