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

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Abstract
Chemical and enzymatic procedures have been employed for the preparation of various phosphorylated derivatives of the ayclonucleoside 9-(1,3-dihydroxy-2-propoxymethyl)adenine, an analogue of the active antiviral agent 9-(1,3-dihydroxy-2-propoxymethyl)guanine (DHPG). In combination with the previously reported 2'', 3''-seco nucleosides and their phosphates and cyclic phosphates (Stolarski et al., Z. Naturforsch. 41c, 758-770, 1986), this made available a broad class of acyclonucleosides and nucleotides, the acyclic moieties of which are capable of mimicing the ribose and 2''-deoxyribose rings. The solution conformation of the foregoing were determined with the aid of 1H, 13C and 31P NMR, and compared with those of DHPG and 9-(hydroxyethoxymethyl)guanine (Acyclovir, ACV). Particular attention was devoted to conformations about C-O bonds in different acyclic fragments, which demonstrated well-defined differences between 2'',3''-seco derivatives on the one hand (conformational "rigidity") and derivatives with DHP and AC acyclic chains on the other (rotation about the C(1'')-O(4'') bond). The overall results are in good general agreement with reported crystal structures, and are compared with those obtained by quantum mechanical calculations. The conformational features of the various compounds are also discussed in relation to their substrate and/or inhibitor properties in a number of enzyme systems, including adenosine deaminase, phosphodiesterases, nuclease P1, 3''-nucleotidase and herpes virus type 1 thymidine kinase.

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