Synthesis and antiviral activity of certain nucleoside 5'-phosphonoformate derivatives

Abstract

(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 nucleoside 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 .mu.M.