Synthesis, structure, and antitumor and antiviral activities of a series of 5-halouridine cyclic 3',5'-monophosphates.
A series of potential prodrug 5-halouridine 3',5'-cyclic monophosphates (5-X-cUMPs, X = F, Cl, Br, I, 1-4) has been prepared and tested for antitumor activity against murine leukemia L1210/0 and human lymphoblast Raji/0 cells and their deoxythymidine kinase deficient (TK-) counterparts, as well as for antiviral activity in primary rabbit kidney cells infected with herpes simplex virus type 1 or 2, vaccinia virus, or vesicular stomatitis virus. The 5-halopyrimidine bases, nucleosides (5-X-U), and 5'-monophosphates (5-X-UMP) were tested for comparison. 5-F-cUMP (1) showed reasonably potent inhibition of tumor cell proliferation (ID50 = 0.33-1.6 micrograms/mL), while the remaining diesters displayed ID50's ranging from 210 to greater than 1000 micrograms/mL. 5-F-cUMP was 70- to 300-fold less active than 5-F-dU in the same systems. With TK- L1210 cells, 5-F-cUMP was as potent as with the normal (L1210/0) line but was about fourfold less active with TK- Raji cells compared to Raji/0 cells. The 5-X-cUMPs showed little potency as antivirals. A single-crystal X-ray analysis of the ammonium salt of 5-I-cUMP confirmed its structure and showed the conformation of the phosphate ring to be the expected chair. The ribose pucker is near 3(4)T, and the torsion angle about the beta-glycosidic N(1)-C(1') bond is in the syn range (-84.8 degrees).
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D007939:Leukemia L1210 / Q000188:drug therapy; D051379:Mice; D008968:Molecular Conformation; D009712:Nucleotides, Cyclic / Q000494:pharmacology*; D011494:Protein Kinases / Q000032:analysis; D011817:Rabbits; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship; D014500:Uracil Nucleotides / Q000494:pharmacology*; D014542:Uridine Monophosphate / Q000494:pharmacology*; D014616:Vaccinia virus / Q000187:drug effects; D014961:X-Ray Diffraction
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D009712:Nucleotides, Cyclic; D014500:Uracil Nucleotides; C045338:cyclic 3',5'-uridine monophosphate; D014542:Uridine Monophosphate; D011494:Protein Kinases