Conformation and Antiherpes Activity of 3′- and 5′-Azido and Amino Analogs of 5-Methoxymethyl-2′-Deoxyuridine

Antiviral Activity of Bicyclic Pyrimidine Nucleosides

“…The compounds 2, 3, 5d, 5e and 7, the compounds 9a, 9b and 12 derived from diethyl malonate coupling and the compounds 13 to 16 were each tested against HIV-1 and HIV-2, but found to be either inactive (50% effective concentration: >300IlM) or only slightly active; (EC so of 3'-azido-P, 7: 200IlM; EC so of the diethyl malonate derivative of AZT, 9b: 401lM, sc., AZT, 0.016IlM). The 3'-azido derivatives of 5-hydroxymethyl-2' ,3'-dideoxyuridine (Li et al, 1994), and the 5-methoxymethyl analogue (Tourigny et al, 1989), both prepared by the method described earlier (Loakes et al, 1995) were also found to be inactive against HIV-1. Fig.…”

Relationship between Conformation and Antiviral Activity-II. 5-Methoxymethyl-2′-deoxycytidine and 5-methoxymethyl-N4-methyl-2′-deoxycytidine

“…incorporation into the DNA inhibits genome replication (Gupta et al, 1989(Gupta et al, , 1991Aduma et al, 1991a). In addition, perturbations of dNTP pools (precursors required for DNA synthesis) on treatment with MMdCyd plus H 4dUrd also contribute to the antiviral activity (Gupta et aI., 1989(Gupta et aI., , 1991Aduma et al, 1991b).The complete loss of antiviral activity by alkylation at the N 4-position of MMdCyd was unexpected and surprising.…”

“…In marked contrast, MMdCTP is preferentially utilized by HSV-1 DNA polymerase and is also a competitive inhibitor of the viral enzyme with respect to dCTP (Gupta et al, 1991;Aduma et al, 1991a).Thus, even if N 4-Me-MMdCMP could be converted to N 4-MeMMdCTP in HSV-infected VERO cells, its lack of affinity for the viral DNA polymerase suggests that viral replication most likely would not be impeded. Studies from our laboratory have shown that the conformation of the deoxyribose moiety is important in determining substrate specificity towards the HSVinduced thymidine kinase Tourigny et al, 1989).Therefore, the crystal structure of MMdCyd and N 4-Me-MMdCyd was determined (Jia et aI., 1990(Jia et aI., , 1990a. Interestingly, and unexpectedly, the conformation of the deoxyribofuranose ringe in MMdCyd and N 4-Me-MMdCyd was found to be different.…”

Structure and conformation of 5-methoxymethyl-N4-methyl-2'-deoxycytidine

“…Since phosphorylation is an essential step for the antiherpes activity of the pyrimidine nucleoside analogs (DeClercq, 1982;Gupta, Tourigny, Stuart, DeClercq, Quail, Ekiel, E1-Kabbani & Delbaere, 1987), it was felt that one possible reason for the loss of bioactivity of N4-methyl-MMdCyd may be that the conformation of the molecule has been altered. This hypothesis is based on studies which have shown that the conformation of the deoxyribofuranose moiety is important in determining substrate specificity towards the viral enzyme (E1-Kabbani, Ekiel, Delbaere, Quail, Ekiel, E1-Kabbani, Tourigny, Delbaere, Stuart & Gupta, 1986;Quail, Tourigny, Delbaere, E1-Kabbani, Stuart & Gupta, 1988;Gupta et al, 1987;Tourigny, Stuart, Ekiel, Aduma & Gupta, 1989;Jia, Tourigny, Stuart, Delbaere & Gupta, 1990). The crystal structure of N4-methylMMdCyd was determined by X-ray diffraction analysis.…”