CHEMISTRY OF PURINES AND PYRIMIDINES 103 



man (see Bailey-^'^ and Lazarow'^^). In 1864, Baeyer^ transformed alloxan 

 into barbituric acid^^^ (2,4,6-trihydroxypyrimidine), the total synthesis of 

 which (from urea and malonic acid) was carried out by Grimaux fourteen 

 years later.^^" The barbiturates are the best known of the hypnotics and 

 sedatives; barbital (5,5-diethylbarbituric acid) and phenobarbital (5- 

 ethyl-5-phenylbarbituric acid) have been in popular use since the first of 

 the two was introduced^"*^ into clinical practice in 1903 (see also Goodman 

 and Gilman242). 



A single change in the structure of uracil, i.e., the substitution of its 2- 

 hydroxy by mercapto, gives rise to a compound, 2-thiouraciP'*^'^'*^ which 

 possesses several important biological properties. For example, 2-thio- 

 uracil and certain of its 4-aIkyl derivatives are effective in the treatment 

 of hyperthyroidism and thyrotoxicosis in man.^''^"^^^ Studies of antithyroid 

 activity and structure of substituted thiouracils have been made,^^^ -^^^ and 

 it has been suggested that these compounds may prevent iodination of 

 thyroxine precursors.^*^ The mode of action of these drugs is still a mystery. 

 Better understood, however, is the 2-thiouracil inhibition of E. coli, since 

 this bacteriostatic action is prevented by uracil.^^^ Uracil also causes a 

 reversal of the 2-thiouracil inhibition of tobacco mosaic virus biosyn thesis. ^^^ 

 Thiouracil may therefore be classified as an antimetabolite and its antago- 

 nism by uracil may be a reflection either of the role of uracil as a component 

 of certain enzyme systems (see above) or of the nucleic acids. (For a dis- 

 cussion of antimetabolites and chemotherapy, see the literature^^^'"''.) 



"' C. C. Bailey, Vitamins and Hormones 7, 365 (1949). 



"8 A. Lazarow, Physiol. Revs. 29, 48 (1949). 



2" Beilstein, 24, 467 (1936). 



240^1. E. Grimaux, Bull. soc. chim. (Nouv. Sdr.) 31, 146 (1879); Compt. rend. 87, 752 



(1878). 

 "1 E. Fischer and v. Mering, Chem. Cenlr. 74, I, 1155 (1903). 

 "^ L. Goodman and A. Gilman, "The Pharmacological Basis of Therapeutics," p. 126. 



Macmillan, New York, 1941. 

 2« Beilstein, 24, 323 (1936). 



2" H. L. Wheeler and H. S. Bristol, Am. Chem. J. 33, 448 (1905). 

 2^5 H. L. Wheeler and L. M. Liddle, Am. Chem. J. 40, 547 (1908). 

 "« E. B. Astwood, /. Am. Med. Assoc. 122, 78 (1943) ; Harvey Lectures 40, 195 (1945). 

 2" H. P. Himsvvorth, Lancet ii, 465 (1943) ; see also p. 483. 

 "8 W. W. van Winkle, Jr., S. M. Hardy, G. R. Hazel, D. C. Hines, H. S. Newcomer 



E. A. Sharp, and W. N. Sisk, /. Am. Med. Assoc. 130, 343 (1946). 

 2" G. W. Anderson, I. F. Halverstadt, W. H. Miller, and R. O. Roblin, Jr., /. Am. 



Chem. Soc. Q7, 2197 (1945). 

 "» R. H. Williams and G. A. Kay, A7n. J. Med. Sci. 213, 198 (1947). 

 "1 W. H. Miller, R. O. Roblin, Jr., and E. B. Astwood, /. Am. Chem. Soc. 67, 2201 



(1945). 

 2" F. B. Strandskov and O. Wyss, /. Bacleriol. 50, 237 (1945). 

 2" B. Commoner and F. Mercer, Nature 168, 113 (1951); Arch. Biochem. and Biophys. 



35,278 (1952). 



