Synthesis and Antitumor Activities of 5'-O-Aminoacyl-3'-O-benzyl Derivatives of 2'-Deoxy-5-fluorouridine and Related Compounds

Various O-alkyl derivatives of 2'-deoxy-5-fluorouridine (FUdR) were synthesized and their antitumor activities in mice bearing sarcoma 180 (s.c.-p.o.) were evaluated in terms of the ED50 values (mg/kg/d). Most of these compounds were superior to FUdR in antitumor activity. In particular, the antitumor activity of 3'-O-(p-chloro-benzyl)-FUdR (3e) (ED50 =0.87mg/kg/d) was as much as 100 times that of FUdR (ED50=84mg/kg/d). Further, various 5'-O-aminoacyl derivatives of 3e were synthesized and evaluated in terms of ED50 value and therapeutic index (T.I.). Both the ED50 value (0.41mg/kg/d) and the T.I. (4.18) of 3'-O-(p-chlorobenzyl)-5'-O-glycyl-FUdR hydrochloride (6a) were significantly improved, compared with those of 3e and FUdR. FUdR plasma concentration after a single p.o. dosing of 6a was maintained for as long as 24h.