Thionucleosides

Abstract: We present the synthesis and the study of properties of a new series of modified oligonucleotides, namely 4'-thio-oligo-beta-D-ribonucleotides (4'-S-RNA). Homo-oligonucleotides of this class (4'-SU6 and 4'-SU12) were prepared from the previously known thionucleosides using the phosphoramidite methodology. The comparison of the substrate properties of 4'-SU6 and its natural analog U6 with respect to four nucleases indicates that the former is much more resistant than the latter. Such resistance to nucleases in addition to relatively high Tm values for 4'-SU12 hybridized with Poly(A) show that these new 4'-S-RNA are good candidates for potential antisense effects. The oligonucleotides 4'-SU6 and 4'-SU12 have been also evaluated as non sequence specific inhibitors of HIV-1 reverse transcriptase. All available evidences, based primarily on fluorescence measurements, are consistent with the binding of 4'-SU6 and 4'-SU12 to RT at a site which is different from the polymerase site of the enzyme.

Abstract: The synthesis of 2',3'-dideoxy-3'-C-(hydrorymethyl)-4'-thionucleosides is described. For the synthesis of the carbohydrate part, the configuration of the secondary hydroxyl group in (2S,3R)-1-O-(p-bromobenzyl)-3-(2'-propenyl)-1,2,4-butanetriol (1) was inverted using Mitsunobu reaction conditions, after which the primary hydroxyl group in product 2 was regioselectively benzoylated using phase-traasfer catalysis. Oxidative cleavage of the allylic double bond, followed by ring closure and exchange of the p-bromobenzyl protecting group gave the methyl furanoside derivative 5, which was further converted to the corresponding dibenzyl dithioacetal 6