Studies on antitumor agents. 8. Antitumor activities of O-alkyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine and 2'-deoxy-5-fluorouridine.

O-Benzyl and O-ethyl derivatives of 2'-deoxy-5-(trifluoromethyl)uridine (F3Thd) and 2'-deoxy-5-fluorouridine (FUdR) were synthesized. The oral antitumor activity of the compounds against sarcoma 180 in mice was examined. The 5'-O-ethyl (3b), 3'-O-ethyl (3c), 5'-O-benzyl (3e), and 3'-O-benzyl (3f) derivatives of F3Thd were 4-fold more active than F3Thd itself. Among the substituted-benzyl derivatives of F3Thd, 3'-O-(p-chlorobenzyl)-F3Thd (3h) showed the highest activity, with an ED50 less than one-tenth of that of F3Thd. The activities of 5'-O-benzyl (7c) and 3'-O-benzyl (7d) derivatives of FUdR were equal to those of the effective O-alkyl derivatives of F3Thd.