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Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-?-fluoro-2'-?-C-methyl Guanosine Phosphoramidate Prodrug.

ABSTRACT: A novel 2',3'-dideoxy-2'-?-fluoro-2'-?-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 ?M) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC₅₀ = 0.39-1.1 ?M) against the HCV genotype (GT) 1a, 1b, 2a, and 1b S282T replicons.

SUBMITTER: Yu W

PROVIDER: S-EPMC5467188 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-α-fluoro-2'-β-C-methyl Guanosine Phosphoramidate Prodrug.

Yu Wenquan W Li Ertong E Lv Zhigang Z Liu Ke K Guo Xiaohe X Liu Yuan Y Chang Junbiao J

ACS medicinal chemistry letters 20170501 6

A novel 2',3'-dideoxy-2'-α-fluoro-2'-β-C-methyl-6-methoxy guanosine (8) and its phosphoramidate prodrug (1) have been designed and synthesized. Their biological activity was evaluated in both cytotoxicity and cell-based HCV replicon assays. Neither compounds exhibited cytotoxicity up to the highest concentration tested (100 μM) in the Huh-7 cell line. The prodrug (1) displayed nanomolar level antiviral activity (EC50 = 0.39-1.1 μM) against the HCV genotype ...[more]

PMID: 28626533

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Project description:Derivatives of 3-amino-3,6-dideoxyhexoses are widespread in Nature. They are part of the repeating units of lipopolysaccharide O-antigens, of the glycan moiety of S-layer (bacterial cell surface layer) glycoproteins and also of many antibiotics. In the present study, we focused on the elucidation of the biosynthesis pathway of dTDP-alpha-D-Quip3NAc (dTDP-3-acetamido-3,6-dideoxy-alpha-D-glucose) from the Gram-positive, anaerobic, thermophilic organism Thermoanaerobacterium thermosaccharolyticum E207-71, which carries Quip3NAc in its S-layer glycan. The biosynthesis of dTDP-alpha-D-Quip3NAc involves five enzymes, namely a transferase, a dehydratase, an isomerase, a transaminase and a transacetylase, and follows a pathway similar to that of dTDP-alpha-D-Fucp3NAc (dTDP-3-acetamido-3,6-dideoxy-alpha-D-galactose) biosynthesis in Aneurinibacillus thermoaerophilus L420-91(T). The ORFs (open reading frames) of interest were cloned, overexpressed in Escherichia coli and purified. To elucidate the enzymatic cascade, the different products were purified by HPLC and characterized by NMR spectroscopy. The initiating reactions catalysed by the glucose-1-phosphate thymidylyltransferase RmlA and the dTDP-D-glucose-4,6-dehydratase RmlB are well established. The subsequent isomerase was shown to be capable of forming a dTDP-3-oxo-6-deoxy-D-glucose intermediate from the RmlB product dTDP-4-oxo-6-deoxy-D-glucose, whereas the isomerase involved in the dTDP-alpha-D-Fucp3NAc pathway synthesizes dTDP-3-oxo-6-deoxy-D-galactose. The subsequent reaction steps of either pathway involve a transaminase and a transacetylase, leading to the specific production of nucleotide-activated 3-acetamido-3,6-dideoxy-alpha-D-glucose and 3-acetamido-3,6-dideoxy-alpha-D-galactose respectively. Sequence comparison of the ORFs responsible for the biosynthesis of dTDP-alpha-D-Quip3NAc revealed homologues in Gram-negative as well as in antibiotic-producing Gram-positive bacteria. There is strong evidence that the elucidated biosynthesis pathway may also be valid for LPS (lipopolysaccharide) O-antigen structures and antibiotic precursors.

Dataset Information

Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-?-fluoro-2'-?-C-methyl Guanosine Phosphoramidate Prodrug.

Publications

Synthesis and Anti-HCV Activity of a Novel 2',3'-Dideoxy-2'-α-fluoro-2'-β-<i>C</i>-methyl Guanosine Phosphoramidate Prodrug.

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