Studies On The Synthesis Of Novel Nucleoside Analogues

In the search for novel nucleoside analogues as antiviral agents, various modifications of nucleosides on both sugar and heterocyclic moieties have been extensively studies. We have synthesized novel purine analogues by solid-phase synthesis and the 2% 3'-dideoxy -nucleosides via three routes. One of nucleosides has been prepared by the treatment of protected 2'-deoxy-2'-fluoro-5-methyl- P -L-arabinofuranosyl uracil with dimethyl dicarboxylate biphenyl (DDB), which has unique feature of ester-linkaged antiviral DDB and nucleosides.1) After reviewed the recent advances in the synthesis, structural modification of nucleoside analogues and studies of their antiviral activity, we designed to prepare novel nucleoside analogues by modifying the sugars and the bases.2) Purine analogues were synthesized by using solid-phase method. The Merrifield resin was treated with 3,4-dihydro-2H-pyran-2-methanol to give the desired THP-linked resin. 2,6-Dichloropurine was loaded onto this resin, and the different substituents were sequentially introduced owing to different reactivities of the chlorine substituents on nucleoside bases. The final product was cleaved from the resin using a standard acidic cleavage protocol (Scheme 1). Six novel 2,6-disubstituted purines were synsized.3) A series of nucleoside analogues were synthesized by using the tetra-O-acetyl-D-ribofuranose and a Lews acid for the activation of the sugar portion in the condensation with silyl bases by the Vorbriiggen method.4) The 2',3'-dideoxysugar was synthesized from L-glutamic acid by three different methods (Scheme 2,3,4), and then reacted with heterocycles to gain2',3'-dideoxynucleosides. We developed the new method (Scheme 4), in which (S)-(+)- Y -Ethoxycarbonyl butyrolactone is reduced by DIBAL-H directly and an acetyl group was used as the protected group to give the final product in high yield.5) Dimethyl dicarboxylate biphenyl (DDB) is a widely used highly effective anti-hepatitic drug with considerable low toxicity, but it is not soluble. 2'-Deoxy-2'-fluoro-5-methyl- 3 -L-arabinofuranosyl uracil was reported as a potent antiviral agent against HBV. We synthesized the nucleoside analogue, which couple uracil and DDB and for the studies of its anti-HBV activity (Scheme 5).6) We have synthesized 75 compounds and 46 of them were not reported in the literature. They were confirmed by elemental analysis, 1H NMR, UV and LC-MS spectra. The evaluation of their antiviral activities is still in progress.