Synthesis and antitumor and antiviral properties of 5-alkyl-2'-deoxyuridines, 3',5'-cyclic monophosphates, and neutral cyclic triesters.
A series of 5-alkyl-2'-deoxyuridine 3',5'-cyclic monophosphates (5-R-cdUMP's, R = Et, i-Pr, n-Pr, n-Bu, n-Pent, n-Hex, n-Oct) was prepared and tested in culture systems as antitumor and antiviral agents in comparison to the 5-alkyl-2'-deoxyuridines (5-R-dUrd's) themselves. Only the 5-Et- and 5-n-Bu-cdUMP showed appreciable cytostatic activities against murine L1210 and human lymphoblast Raji cells (ID50 range: 28-82 micrograms/mL). 5-Et-dUrd itself was much more active (ID50 = 1.6 and 2.9 micrograms/mL). The 5-i-Pr-, and 5-n-Bu-dUrd's were inactive, but activity increased again for groups with chain lengths of five carbons or greater. 5-Et-cdUMP and 5-Et-dUrd had greatly reduced activities against deoxythymidine kinase deficient (TK-) L1210 and Raji cells. 5-Et-cdUMP evidently is not an efficient prodrug source of the corresponding 5'-monophosphate where the TK- cells are concerned. Of the 5-R-cdUMP's, 5-Et-cdUMP displayed reasonably good antiviral potency against herpes simplex types 1 and 2 (MIC50, mostly 7-70 micrograms/mL) and vaccinia virus (MIC, 70 micrograms/mL). The activity was nonetheless 10- to 100-fold less than that for 5-Et-dUrd. The other 5-R-dUrd's generally showed decreasing antiviral activity with increasing 5-R chain length. Methyl and/or benzyl neutral triesters of certain 5-R-cdUMP's were inactive as antivirals and largely inactive against tumor cells in culture. In contrast to the 5'-monophosphates, the 5-R-cdUMP's failed to inhibit thymidylate synthetase from L1210 cells.
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002460:Cell Line; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D009682:Magnetic Resonance Spectroscopy; D051379:Mice; D009712:Nucleotides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000032:analysis; D013940:Thymidylate Synthase / Q000037:antagonists & inhibitors; D014500:Uracil Nucleotides / Q000138:chemical synthesis*; D014542:Uridine Monophosphate / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000494:pharmacology
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009712:Nucleotides, Cyclic; D014500:Uracil Nucleotides; D014542:Uridine Monophosphate; D013940:Thymidylate Synthase; D013937:Thymidine Kinase