454 R. E. HANDSCHUMACHER AND A. D. WELCH 



afford a means of influencing rates of cellular reproduction. The implica- 

 tions of such external control techniques to the therapy of bacterial, viral, 

 and neoplastic diseases are obvious. Third, they enable certain analogs of 

 the purines and pyrimidines to be introduced into the nucleic acids, a fea- 

 ture which provides an opportunity for studying the functional significance 

 of various portions of these macromolecules with particular reference to 

 the role of certain types of RNA in the activation of amino acids for protein 

 synthesis, and the role of specific varieties of DNA in the transmission of 

 genetic information in cellular reproduction. In this chapter are discussed 

 a selection of some of the more interesting compounds shown (a) to have 

 a relatively specific action on the biosynthesis and incorporation of purine- 

 or pyrimidine-containing compounds, (b) to be incorporated themselves 

 into the nucleic acids, or (c) to resemble a component of the nucleic acids 

 and to possess striking biological activity. Compounds will be discussed 

 individually in groups chosen either for site of action or general structure 

 (see Table of Contents). 



Of the agents to be discussed, several have been designed and synthesized 

 with the specific objective of attaining a blockade of a known reaction or 

 sequence of reactions in nucleotide synthesis. Indeed, certain predictions 

 now are possible concerning some of the structural alterations which it is 

 reasonable to consider, for several compounds have been prepared on this 

 basis which are sufficiently similar to normal metabolites that they either 

 function in or inhibit specific metabolic reactions. Typical of these replace- 

 ments has been the substitution of halogens for a hydrogen atom or a methyl 

 group in position 5 of the pyrimidines (e.g., fluoro, chloro, bromo, and iodo 

 derivatives of uracil), replacement of oxygen functions by sulfur or amino 

 groups (e.g., mercaptopurine, thioguanine, aminopterin), or alteration in 

 basic ring structures by replacement of carbon by nitrogen (e.g., azaguanine, 

 azauracil, azathymine). The biological activities of some of these and of 

 other compounds were discovered through screening procedures designed 

 to disclose inhibitory activity for the growth of microorganisms or neoplas- 

 tic tissue, and only later were specific actions on nucleic acid metabolism 

 uncovered (e.g., with azaserine and 6-diazo-5-oxo-L-norleucine). Many ex- 

 perimental techniques for screening potential purine and pyrimidine anti- 

 metabolites have been described and these will continue to be of great value 

 in further studies in this area. 15 At present these systems are primarily 

 capable of identifying compounds which alter the biosynthesis of nucleo- 

 tides. It is to be hoped, however, that with the aid of recently developed 



1 G. H. Hitchings and G. B. Elion, Cancer Research Suppl. 3, 66 (1955). 



2 J. D. Davidson and B. B. Freeman, Cancer Research Suppl. 3, 97 (1955). 



3 G. A. LePage and J. L. Greenlees, Cancer Research Suppl. 3, 102 (1955). 



4 C. Heidelberger and R. A. Keller, Cancer Research Suppl. 3, 106 (1955). 



5 J. E. Stone and V. R. Potter, Cancer Research 17, 794 (1957). 



