Synthesis and enzymatic transformations of 5-halo-6-methoxy-5,6-dihydro derivatives of 5-[1-methoxy-2-halo (or 2,2-dihalo)ethyl]-2'-deoxyuridines as potential herpes simplex virus inhibitors.
The 5-halo-6-methoxy-5,6-dihydro derivatives of 5-[1-methoxy-2-halo(or 2,2-dihalo)ethyl]-2'-deoxyuridines (3-12) were synthesized and investigated as potential anti-herpes agents. These 5,6-dihydro derivatives were designed to act as potential prodrugs to 5-[1-methoxy-2-halo(or 2,2-dihalo)ethyl]-2'-deoxyuridines (2a-e), with enhanced metabolic stability, and ready conversion to the parent molecules. These 5,6-disubstituted-5,6-dihydro analogs are stable to E. coli thymidine phosphorylase, and undergo regeneration of the 5,6-olefinic bond to provide parent moieties (2a-e), upon incubation with glutathione at 37 degrees C. The compounds (3-12) themselves were found to be non-inhibitory against herpes simplex virus type-1 (HSV-1), likely due in part to their inability to undergo conversion to parent compounds in cell culture medium.
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002522:Chlorocebus aethiops; D002855:Chromatography, Thin Layer; D004396:Coloring Agents / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology*; D015195:Drug Design; D004926:Escherichia coli / Q000201:enzymology; D009682:Magnetic Resonance Spectroscopy; D008956:Models, Chemical; D018139:Simplexvirus / Q000187:drug effects* / Q000378:metabolism; D013696:Temperature; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D013939:Thymidine Phosphorylase / Q000737:chemistry; D014709:Vero Cells
D000998:Antiviral Agents; D004396:Coloring Agents; D013778:Tetrazolium Salts; D013844:Thiazoles; D013939:Thymidine Phosphorylase; C022616:thiazolyl blue; D003857:Deoxyuridine