| Abstract
| - Various d- and l-thietanose nucleosides were synthesized from d- and l-xylose. The four-membered thietanering was efficiently synthesized by the cyclization of 1-thioacetyl-3-mesylate (4/38) under basic conditions.Condensation with various heterocyclic bases was conducted via Pummerer-type rearrangement to affordvarious nucleoside derivatives. Among the synthesized nucleosides, d-uridine (23), d-cytidine (24), d-5-fluorocytidine (25), and l-cytidine (52) analogues showed moderate anti-HIV activity, with EC50 = 6.9,1.3, 5.8, and 14.1 μM, respectively. However, these four nucleoside analogues are cytotoxic in peripheralblood mononuclear and CEM cells. The other nucleosides are neither active nor cytotoxic. Interestingly, theoxetanocin A analogue 33 was not active. Comparison of the minimized reverse transcriptases (RTs)complexed with the corresponding triphosphates of the cytidine analogue 24 and the adenosine analogue 33by molecular modeling studies showed that there is no difference in the binding mode of the triphosphateof the cytidine analogue 24 to the active site of HIV-1 RT from that of the triphosphate of the adenosineanalogue 33. Modeling studies on the initial monophosphorylation step by deoxycytidine kinase showedthat the catalytic efficiency of phosphorylation through a nucleophilic attack of the 4‘-hydroxyl group ofthietanose on the γ-phosphate of ATP is diminished in the case of l-cytidine analogue (52) due to theincreased distance between the 4‘-hydroxyl group and the γ-phosphate.
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