Journal of Medicinal Chemistry vol:29 issue:7 pages:1243-9
The title diesters (11-15; halo substituents F, Cl, Br, I) were prepared by DCC-induced cyclization of the precursor 5'-monophosphate or direct halogenation of the 2'-deoxyuridine 3',5'-cyclic monophosphate. Antitumor activities of 11-15 in cell systems (L1210 and Raji/0) were compared to those of the corresponding nucleosides and 5'-monophosphates. Thus, the 5-F- and 5-CF3-2'-deoxyuridines proved to be highly active derivatives [ID50 values (microgram/mL) for L1210, 0.002 and 0.06, respectively], with the 5'-monophosphates showing comparable potencies. The corresponding 3',5'-cyclic monophosphate diesters were 20-30 times less potent but nonetheless highly cytostatic. All derivatives including 11-15 had greatly increased ID50 values for the thymidine kinase deficient (TK-) L1210 and Raji cells. The 3',5'-cyclic diesters (11-15) evidently are not efficient prodrug sources of the nucleoside 5'-monophosphates in TK- cells. They also proved to be 100- to 2000-fold less efficient inhibitors of L1210 thymidylate synthetase than were the 5'-monophosphates. The 5-substituted 2'-deoxyuridines and their 5'-monophosphates were potent inhibitors of herpes simplex virus (MIC50 mostly 0.07-10 micrograms/mL) and vaccinia virus (MIC50 0.07-0.2 microgram/mL), with antiviral activity decreasing in the order 5-I, 5-Br greater than 5-CF3 greater than 5-Cl greater than 5-F. The 3',5'-cyclic monophosphates (11-15) were for the most part 10- to 40-fold less active than the 5'-monophosphates in the virus assay systems (e.g., MIC50 for the 5-Br and 5-I derivatives ranged 1-20 micrograms/mL). By contrast 11-15 were considerably more potent inhibitors of vaccinia virus growth (MIC50 0.4-2 micrograms/mL). As the neutral 3',5'-cyclic methyl phosphate triesters (16-18), the 5-I and 5-Br compounds were less potent in antiviral and cytostatic agents than the 3',5'-cyclic diesters, while the 5-iodo benzyl triester was in several cases as active as the 3',5'-cyclic diester. The title compounds (11-15) appear to require extracellular hydrolysis to the nucleoside before functioning as antitumor or antiviral agents.