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 = 0.87 mg/kg/d) was as much as 100 times that of FUdR (ED50 = 84 mg/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 (0.41 mg/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 24 h.
Uemura
A
A
Hanno Research Center, Taiho Pharmaceutical Co., Ltd., Saitama, Japan.
Tada
Y
Y
Takeda
S
S
Uchida
J
J
Yamashita
J
J
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000138:chemical synthesis* / Q000494:pharmacology*; D004354:Drug Screening Assays, Antitumor; D005467:Floxuridine / Q000031:analogs & derivatives* / Q000097:blood; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012510:Sarcoma 180 / Q000188:drug therapy / Q000378:metabolism; D013329:Structure-Activity Relationship
D000964:Antimetabolites, Antineoplastic; D005467:Floxuridine