316 P. Alexander, S. F. Cousens and K. A. Stagey 



the crosslinks. The situation here is too complex to be 

 analysed by the methods available to us. 



Molecules with hidden breaks appear to retain all their 

 normal properties and it is conceivable that they continue to 

 exercise their biological function but that they transmit a 

 slightly altered code. 



Summary 



Chemical considerations suggest that the essential charac- 

 teristic of the radiomimetic alkylating agents (i.e. sulphur 

 and nitrogen mustards, epoxides, ethylene imines and esters 

 of methanesulphonic acid) is their ability to esterify anions 

 such as the carboxyl groups of proteins and the phosphate 

 groups of DNA and RNA. These substances can also alkylate 

 amino and sulphydryl groups. These reactions, although they 

 undoubtedly occur in the cell, are unlikely to be of biological 

 importance since many other substances which can react with 

 amino and SH groups but not with anions are biologically 

 inactive. 



In proteins, the radiomimetic alkylating agents react with 

 all the available groups such as NHg, SH and COOH but in 

 DNA only esterification of the phosphate groups is found 

 unless the reagent is present in excess. The steric configura- 

 tion of the DNA probably screens the purine and pyrimidine 

 bases and this is confirmed by the failure of substances, which 

 readily combine with amino groups in proteins, to react with 

 DNA under physiological conditions. Probably the reason 

 why the radiomimetic alkylating agents are such eff'ective 

 mutagens is because they can combine with the most vulner- 

 able group in the DNA, the phosphate group. 



Esterification of phosphate groups is also the most pro- 

 minent reaction when a nucleoprotein (herring sperm heads) 

 is treated with nitrogen mustards. The protamine does not 

 block the phosphate groups in such a way as to prevent 

 alkylation. 



The polyfunctional alkylating agents, which are much more 

 active, crosslink DNA. In dilute solution the crosslinks are 



