The biological activity of substituted pyrimidines.

Recent investigations have shown that the animal microorganism, Tetrahymena geleii, requires an exogenous source of pyrimidine for growth (1). This requirement can be met by the addition of cytidylic acid or uracil to the medium (2). Cytosine and thymine are without activity. The failure to utilize the latter two free bases was interpreted as indicating a block in the ability of the organism to carry out the riboside linkage in these two cases. The utilization of uracil, however, demonstrates the ability of the organism to carry out the specific riboside linkage to form the nucleoside and nucleotide of uracil and also its ability (and obligation) to substitute an amino group for the keto group in the 6 position without breaking the riboside linkage. Of the naturally occurring pyrimidine bases, therefore, uracil was found to be the only one which would satisfy the needs of this organism. A systematic testing of various substituted pyrimidine bases over wide ranges of concentrations offers a means of evaluating the physiological importance of the positions and radicals. Thii, in turn, may help us to understand better the particular enzymes involved. The substituted pyrimidines can be divided into four categories: (1) they may replace uracil; (2) they may exert sparing action, so that the amount of uracil required for optimal growth is reduced; (3) they may exhibit inhibition even in the presence of uracil; and (4) they may be inert. The purpose of this communication is to report the results obtained on twenty-three substituted pyrimidine bases in regard to their activities when tested with Tetrahymena. We are deeply grateful to Dr. George H. Hitchings and his colleagues at the Wellcome Research Laboratories for generously supplying us the pyrimidines used. Without their cooperation this study would have been impossible.