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



are of interest because they are slowly cleaved to mercaptopurine in the intestine 

 following oral administration. 208 ' 210 ' 2U Similarly, 6-(l '-methyl -4'-nitro-5'-imidazo- 

 lyl)-thiopurine and the analogous derivative of thioguanine apparently serve as 

 sources of the corresponding thiopurines in vivo 212 - 213 ; these compounds have shown 

 sufficient promise to justify clinical trials which are now in progress. 214 Substitution 

 of selenium for sulfur results in a compound, 6-selenopurine, 215 with increased bio- 

 logical activity against certain microorganisms. 216 Studies with experimental tumors 

 in mice indicate that, in general, selenopurine is less active than mercaptopurine, 217 

 but it profoundly inhibits the incorporation of formate into nucleic acid purines of 

 Ehrlich ascites tumor cells in vitro. 216 



2. Thioguanine 



The guanine analog, thioguanine (2-amino-6-mercaptopurine) (X), was 

 first prepared in 1948. Although the method of synthesis was similar to 

 that described for 6-mercaptopurine, the yields were variable and a satis- 

 factory synthesis involving thiation of guanine by phosphorus pentasulfide 

 in pyridine did not appear until 1955. 218 However, sufficient material was 

 available in the intervening years for demonstration of the marked inhibi- 

 tion of the growth of L. casei by the analog, 160 an effect which could be 

 prevented by adenine, guanine, hypoxanthine, or xanthine at one-tenth 

 the level of thioguanine. 166 Studies with S. faecalis indicated similar inhibi- 

 tion except that xanthine was ineffective as a reversing agent 168 ; strains of 

 these organisms selected for resistance to thioguanine were cross-resistant 

 to 6-mercaptopurine. 167168 Thioguanine was also shown to inhibit the 

 growth of experimental neoplasms in mice at one-twentieth the dosage 

 levels required for mercaptopurine 161 ' 219 ; however, toxicity to the host, 

 manifested as extreme depression of the bone marrow and resultant agranu- 

 locytosis and thrombocytopenia, was observed. Nevertheless, these pre- 

 liminary results led to a clinical trial of thioguanine in human leukemia 107 ; 

 although the results were encouraging, the compound appeared to offer no 

 advantage over mercaptopurine and dosage levels similar to those of mer- 

 captopurine were required, in contrast to the results obtained in mice. 



209 I. Goodman, Federation Proc. 18, 236 (1959). 



210 D. A. Clarke and G. H. Hitchings, Proc. Am. Assoc. Cancer Research 2, 287 (1958). 



211 G. H. Hitchings, J. R. Fouts, F. S. Philips, and S. S. Sternberg, Proc. Am. Assoc. 

 Cancer Research 2, 307 (1958). 



212 G. B. Elion and G. H. Hitchings, Federation Proc. 18, 221 (1959). 



213 G. H. Hitchings and G. B. Elion, Proc. Am. Assoc. Cancer Research 3, 27 (1959). 



214 G. B. Elion, G. H. Hitchings, and R. W. Rundles, Proc. Am. Assoc. Cancer Re- 

 search 3, 18 (1959). 



215 H. G. Mautner, J. Am. Chem. Soc. 78, 5292 (1956). 



216 H. G. Mautner, Biochem. Pharmacol. 1, 169 (1958). 



217 H. G. Mautner and J. J. Jaffe, Cancer Research 18, 294 (1958). 



218 G. B. Elion and G. H. Hitchings, J. Am. Chem. Soc. 77, 1676 (1955). 



219 D. A. Clarke, F. S. Philips, S. S. Sternberg, and C. C. Stock, Ann. N. Y. Acad. 

 Sci. 60, 235 (1954). 



