Synthesis and antiviral activity of certain nucleoside 5'-phosphonoformate derivatives.
(Ethoxycarbonyl)phosphonic dichloride (3) was synthesized by chlorination of bis(trimethylsilyl) (ethoxycarbonyl)phosphonate with thionyl chloride. Adenosine 5'-(ethoxycarbonyl)phosphonate (4), guanosine 5'-(ethoxycarbonyl)phosphonate (5), 2'-deoxyadenosine 5'-(ethoxycarbonyl)phosphonate (18) and 2'-deoxyguanosine 5'-(ethoxycarbonyl)phosphonate (19) were synthesized by coupling of compound 3 with adenosine, guanosine, 2'-deoxyadenosine, and 2'-deoxyguanosine, respectively. Alkaline treatment of 4, 5, 18, and 19 gave the corresponding adenosine 5'-(hydroxycarbonyl)phosphonate (14), guanosine 5'-(hydroxycarbonyl) phosphonate (15), 2'-deoxyadenosine 5'-(hydroxycarbonyl)phosphonate (20), and 2'-deoxyguanosine 5'-(hydroxycarbonyl) phosphonate (21). Treatment of 4 and 5 with methanolic ammonia resulted in the production of adenosine 5'-(aminocarbonyl)phosphonate (12) and guanosine 5'-(aminocarbonyl)phosphonate (13), respectively. The nucleotide analogue 20 exhibited the most potent antiviral activity of this group of nucleotide tested in vitro and was most active against herpes viruses especially HSV-2. The nucleotide analogue 21 had lower, but significant, activity against HSV-2. All of the compounds tested were nontoxic to confluent Vero cells at concentrations as high as 5000 microM.
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis*; D002460:Cell Line; D002522:Chlorocebus aethiops; D017977:Deltaretrovirus / Q000187:drug effects; D017245:Foscarnet; D006863:Hydrogen-Ion Concentration; D007939:Leukemia L1210 / Q000188:drug therapy; D007941:Leukemia P388 / Q000188:drug therapy; D051379:Mice; D009705:Nucleosides / Q000494:pharmacology; D009943:Organophosphorus Compounds; D010746:Phosphonoacetic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018139:Simplexvirus / Q000187:drug effects; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D009705:Nucleosides; D009943:Organophosphorus Compounds; D017245:Foscarnet; D010746:Phosphonoacetic Acid