5'-O-phosphonomethyl-2',3'-dideoxynucleosides: synthesis and anti-HIV activity.
5'-O-Phosphonomethylation of different pyrimidine 2',3'-dideoxynucleosides was accomplished by reaction of the latter with diethyl [(p-toylsulfonyl)oxy]methanephosphonate (1) in the presence of sodium hydride. The base-phosphonomethylated (15-19) and sugar-phosphonomethylated (8-12) derivatives could be readily distinguished by 1H and 13C NMR and MS analysis. Protection of the uracil or thymine residue with a N3-benzoyl group failed to prevent base modification. However, O4-methyl-protected 2',3'-dideoxyuridine readily afforded the 5'-O-phosphonomethylated derivative 12, which was converted to both the 2',3'-didoxyuridine analogue 27 and the 2',3'-dideoxycytidine counterpart 29. The 5'-O-phosphonomethyl derivatives of 3'-deoxythymidine (23), 2',3'-dideoxyuridine, (27), 2',3'-dideoxycytidine (29), 3'-O-methylthymidine (26), and 3'-amino-3'-deoxythymidine (28) did not show an appreciable anti-HIV activity in MT-4 cells. In contrast, the 5'-O-phosphonomethyl derivatives of 3'-deoxy-3'-fluorothymidine (24) and 3'-azido-3'-deoxythymidine (25) inhibited HIV-1 cytopathogenicity by 50% at a concentration of approximately 1 microM.
Laboratory of Pharmaceutical Chemistry, Rega Institute for Medical Research, Leuven, Belgium.
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L
Jie
A
A
Van Aerschot
J
J
Balzarini
G
G
Janssen
R
R
Busson
J
J
Hoogmartens
E
E
De Clercq
P
P
Herdewijn
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002621:Chemistry; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000627:therapeutic use; D015497:HIV-1 / Q000187:drug effects; D006801:Humans; D009943:Organophosphorus Compounds / Q000138:chemical synthesis* / Q000627:therapeutic use; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
D000998:Antiviral Agents; D015224:Dideoxynucleosides; D009943:Organophosphorus Compounds; D018894:Reverse Transcriptase Inhibitors