A Facile, Alternative Synthesis of 4‘-Thioarabinonucleosides and Their Biological Activities

Abstract

4'-Thioarabinonucleosides, which are potential antiviral agents, were synthesized from D-glucose. 1,4-Anhydro-4-thioarabitol (8), which can be derived from diacetone glucose in nine steps, was subjected to Pummerer rearrangement after protection of the hydroxyl groups to give 1-O-acetyl-4-thioarabinose (11), which was condensed with nucleobases to give 4'-thioarabinonucleosides. The 5-substituted-4'-thioaraU (6a-e) derivatives showed anti-HSV-1 activity (ED50 = 0.43-3.50 micrograms/mL). 4'-ThioaraG (6h) and 2,6-diaminopurine 4'-thioarabinonucleoside (4'-thioaraDAP, 6g) showed antiviral activity against several herpes viruses and were particularly potent against human cytomegalovirus (0.010 and 0.022 microgram/mL, respectively).

Preparation of 2,3,5-Tri-O-benzyl-4-thio-L-arabino-furanosides and the Corresponding 4′-Thionucleoside Analogues

“…Ϫ The counterpart of 9 with -xylo configuration has also been used as a key intermediate for the synthesis of adenine nucleosides [12,13] Scheme 1 as well as the enantiomer -9 which served as precursor for several nucleosides. [14,15] The free C-4 hydroxy group of 4 was mesylated at room temperature in pyridine to obtain 5 which exhibits a good leaving group for the following cyclisation step. Earlier [17,18] Results and Discussion and numerous recent publications [5,19] propose sodium iodide and barium carbonate in dry acetone at reflux temperaOur synthesis started with commercially available and ture for this cyclisation.…”

Synthesis of 4′-Thionucleosides as Antitumor and Antiviral Agents

“…The Vorbrüggen reaction of 17 with silylated nucleobases in the presence of Lewis acid and the subsequent deprotection gave 4′-thioarabinonucleosides 18. 29) Introduction of a fluoro group at the 2-position was achieved by treatment of 11 with N,N-diethylaminosulfur trifluoride (DAST) to give the 2-fluorinated compound 19 with retention of the stereochemistry at the reaction site. Similar results reported by Marquez and colleagues suggested that the reaction proceeded by a neighboring group participation of ring sulfur to form an episulfonium ion prior to the nucleophilic attack of fluoride ion.…”

“…We therefore evaluated the anti-herpesvirus activities of the 4′-thio counterparts of these nucleosides by culturing them with several viruses, including human herpes simplex virus types 1 and 2 (HSV-1 and -2), varicella zoster virus (VZV), and human cytomegalovirus (HCMV), followed by analysis with a plaque reduction assay. 29,31,38) The results are summarized in Tables 2 and 3. The 5-substituted-4′-thioaraU derivatives (B=5-methyl, 5-ethyl-and 5-iodouracils) showed anti-HSV-1 activity (ED 50 : 0.43-3.50 µg/mL), but moderate to weak inhibitory activity against HSV-2 and VZV.…”

Cyclic ADP-Carbocyclic-Ribose and -4-Thioribose, as Stable Mimics of Cyclic ADP-Ribose, a Ca²⁺-Mobilizing Second Messenger

“…1), a 4-thioribose analogue of cADPR. 44) It has been recognized that 4′-thionucleosides can be useful bioisosteres of the natural nucleosides, in which the 4-thioribose does not only effectively mimic the ribose of nucleosides, [45][46][47][48][49][50][51] but also the N-4-thioriobosyl linkage is more stable than the corresponding N-ribosyl linkage against both the chemical and enzymatic hydrolysis. 52,53) In addition, the pK a value of cADPtR is expected to be similar to that of cADPR due to the electron-withdrawing property of sulfur atom.…”