Synthesis and Antiviral Evaluation of 4′-C-Azidomethyl-β-D-Ribofuranosyl Purine and Pyrimidine Nucleosides

Abstract

In the search for inhibitors of the replication of RNA viruses, including hepatitis C virus (HCV), the hitherto unknown 4'-C-azidomethyl-beta-D-ribofuranosyl nucleosides of the five naturally occurring nucleic acid bases have been synthesized and their antiviral properties examined. These 4'-C-branched nucleosides were stereospecifically prepared by glycosylation of purine and pyrimidine aglycons with a suitable peracylated 4-C-azidomethyl-D-pentofuranose sugar, followed by removal of the protecting groups. The prepared compounds were tested for their activity against several viruses, but they did not show an antiviral effect.

Nucleoside, Nucleotide, and Non-Nucleoside Inhibitors of Hepatitis C Virus NS5B RNA-Dependent RNA-Polymerase

“…A series of 4′-substituted ribonucleosides having any one of four naturally occurring nucleic acid bases and azido, azidomethyl, ethynyl, allyl, vinyl, alkyl, and alkoxy 4′-substitutents were screened as inhibitors of HCV replication. − The 4′-azidocytidine derivative 19 (R1479, Figure ) was identified as the only active nucleoside (EC 50 = 1.28 μM) that did not also exhibit cytotoxic or cytostatic behavior and was shown to be a chain terminator of RNA synthesis. ,, The S96T amino acid change in the NS5B polymerase produced a 4- to 5-fold resistance to the activity of 19 . Several other 4′-substituted ribonucleosides having either a uridine base or a 4′-ethynyl group were shown to be inhibitors of the NS5B polymerase as their triphosphate derivatives in the isolated enzyme assay, indicating that a blocked phosphorylation path was contributing to their lack of whole cell replicon activity .…”

A review of methods to synthesise 4′-substituted nucleosides

“…The 4′-α-hydroxymethyl unit has also been used to access a variety of 4′-substituted ribose nucleosides (Scheme 3). The hydroxyl can be removed either by radical means 7 or via conversion to the iodide and then hydrogenation 8 to provide methyl analogues such as 12. Substitution of the hydroxyl by treatment with either DAST or TsCl/sodium azide can also be used to access the fluoride and azide analogues respectively.…”

“…Substitution of the hydroxyl by treatment with either DAST or TsCl/sodium azide can also be used to access the fluoride and azide analogues respectively. 8,9 Both the 4′-α-aldehyde and alcohol functional groups have been used to excellent effect to access a wide range of conformationally constrained bicyclic nucleosides (Scheme 4). The reader is directed to the excellent review recently published on this topic for further details.…”

A Rapid Phase Transfer Catalyzed Heteroarylation by C-O Coupling and Ring Opening of Isopropylidene Glycerol in Synthesis of (Pyrazolopyrimidin-4-yloxy)propane-1,2-diols

“…Zoltewicz and others [4][5][6][7] have given a good early review of various methods and compared with other techniques that make use of polar solvents, transition metals and monoelectron transfers. In general, phase transfer catalysis (PTC) can be used for heteroaromatic SN reactions [8][9][10][11]. Chloro group present at position 2 and 4 in pyrimidine has been found reactive towards SN reactions with variety of nucleophilic reagents [12,13].…”