O-ALKYL-5',5'-DINUCLEOSIDE PHOSPHATES AS PRODRUGS OF 3'-AZIDOTHYMIDINE AND CORDYCEPIN

The syntheses of two O-alkyl-5',5'-dinucleoside phosphotriesters 2a and 2b as combined prodrugs of the antiviral drug AZT (1) and the antibiotic agent cordycepin (3) are described. 2a,b were obtained as a 1:1 diastereomeric mixture. The absolute configuration of the isolated diastereomers was determined by NOE NMR experiments and correlated with the migration characteristics on silica gel as well as the P-31-NMR chemical shift. The conformational features of 2b(R) and 2b(S) were determined m deuteriated dodecylphosphocholine micelles in aqueous solution using 2D-NOESY spectra and shown to be dependent on the configuration at phosphorus. Additionally, all new compounds were tested for their antiviral activities in HIV-1-infected CEM C113 and H9 cell systems. Although all compounds were able to significantly inhibit the HIV-1-induced cytopathogenic effect, only the phosphodiester 12 gave a selectivity index (SI(RT) = 2000) comparable to the reference compound AZT (1) (SI(RT) = 3000).