Antimetabolite Activity of Uridine and Cytidine

With the realization in 1940 (1) that structural analogues of a metabolite frequently prevent utilization of that metabolite, it became possible to develop antimetabolites which block specific biosynthetic pathways. By blocking various steps in a biosynthetic pathway, antimetabolites are useful for elucidating intermediary metabolism. It was the object of the present study to investigate the biosynthetic pathway of the pyrimidine moiety of pentose nucleic acid by the use of antimetabolites. Uridine and cytidine were chosen as structural models for the inhibitors. This choice was made because (a) 5chlorouridine inhibits the growth response of Neurospora mutant strain 1298 produced by uridine or cytidine (2) ; (b) labeled uridine and cytidine are incorporated into tissue nucleic acid in the rat (3) ; (c) labeled uracil (4) and cytosine (5) are not incorporated into tissue nucleic acid in rats; (d) Neurospora 1298 is a convenient test organism which requires uracil, uridine, or cytidine for growth (6). Effective use of inhibitors for studying intermediary reactions depends upon the availability of a sufficient number of specific antimetabolites. Therefore several pyrimidine nucleosides were synthesized and tested in the hope that one or more of these might vary in its ability to block enzymatic reactions involved in nucleic acid metabolism. The compounds 5-methyluridine, 5-methylcytidine, 5-aminouridine, diazouridine, 3-methyluridine, and 5-hydroxyuridine were tested for their effect on the growth of the wild type Neurospora and the growth response of Neurospora 1298 produced by uridine, cytidine, or uracil. The synthesis of these compounds will be reported elsewhere (7).