Relationship between structure and antiviral activity of 5-methoxymethyl-2′-deoxyuridine and 5-methoxymethyl-1-(2′-deoxy-β-d-lyxofuranosyl)uracil

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

“…Differences in activity can be rationalized on the basis of altered conformations of the Na-substituent and/or the 5'-CH2OH side chain. Since phosphorylation of the C(5')OH group is required for metabolic activation of the nucleoside, it appears that the molecule is not readily phosphorylated by HSV-induced dCyd/dThd kinase when the group does not have the g+ conformation (Gupta et al, 1987). Furthermore the c/s relationship between the Na-substituent and N(3) may interfere with enzymatic interaction.…”

“…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.…”

Solution Conformations of Some Acyclo Nucleoside and Nucleotide Analogues of Antiviral Acyclonucleosides, and Their Substrate/Inhibitor Properties in Several Enzyme Systems

“…Crystallographic and NMR data have shown that the mutual orientation of the 5'-OH and 3'-OH groups is of key importance in the phosphorylation step [35], Relevant to this is the observation that 5-methoxymethyl-l-(2'-deoxy-ß-D-lyxofuranosyl) uracil [36] in which the cisoidal hydroxyl groups are close to each other, is not phosphorylated by viral TK; whereas 5-methoxymethyl-2'-deoxyuridine, in which the two hydroxyls are widely separated, is a substrate.…”

2',3'-Didehydro-2',3'-dideoxy-5-hydroxymethyluridine

“…2',Y-Didehydro-2',Y-dideoxy-5-hydroxymethyluridine (D4HMUrd), which has the structural features of both D4T and HMdUrd was synthesized as a potential anti-HIV agent. This investigation is part of a series of conformational studies in progress to determine the effect of changes in structure on antiviral activity (Gupta et al, 1987;Jia, Tourigny, Stuart, Delbaere & Gupta, 1990ab;.…”