Synthesis and Antiviral Activity of a Series of 2′-C-Methyl-4′-thionucleoside Monophosphate Prodrugs
The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4′-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses...
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| Published in | Molecules Vol. 25; no. 21; p. 5165 |
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| Main Authors | , , |
| Format | Journal Article |
| Language | English |
| Published |
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06.11.2020
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| Online Access | Get full text |
| ISSN | 1420-3049 1433-1373 1420-3049 1433-1373 |
| DOI | 10.3390/molecules25215165 |
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| Abstract | The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4′-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2-C-methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4′-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom. |
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| AbstractList | The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4′-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2-C-methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4′-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom. The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4'-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2- -methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4'-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom. The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4'-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2-C-methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4'-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom.The NS5B RNA-dependent RNA polymerase of the hepatitis C virus (HCV) is a validated target for nucleoside antiviral drug therapy. We endeavored to synthesize and test a series of 4'-thionucleosides with a monophosphate prodrug moiety for their antiviral activity against HCV and other related viruses in the Flaviviridae family. Nucleoside analogs were prepared via the stereoselective Vorbrüggen glycosylation of various nucleobases with per-acetylated 2-C-methyl-4-thio-d-ribose built in a 10-step synthetic sequence from the corresponding ribonolactone. Conjugation of the thionucleoside to a ProTide phosphoramidate allowed for evaluation of the prodrugs in the cellular HCV replicon assay with anti-HCV activities ranging from single-digit micromolar (μM) to >200 μM. The diminished anti-HCV potency of our best compound compared to its 4'-oxo congener is the subject of ongoing research in our lab and is proposed to stem from changes in sugar geometry imparted by the larger sulfur atom. |
| Author | Dentmon, Zackery W. Kaiser, Thomas M. Liotta, Dennis C. |
| AuthorAffiliation | 2 St. Peter’s College, University of Oxford, Oxford OX1 2DL, UK; thomas.kaiser@spc.ox.ac.uk 1 Department of Chemistry, Emory University, 1521 Dickey Dr., Atlanta, GA 30322, USA; zack.dentmon@emory.edu |
| AuthorAffiliation_xml | – name: 1 Department of Chemistry, Emory University, 1521 Dickey Dr., Atlanta, GA 30322, USA; zack.dentmon@emory.edu – name: 2 St. Peter’s College, University of Oxford, Oxford OX1 2DL, UK; thomas.kaiser@spc.ox.ac.uk |
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| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/33171951$$D View this record in MEDLINE/PubMed |
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| SubjectTerms | Acids Alcohol Amides - chemistry Antiviral Agents - chemical synthesis Antiviral Agents - pharmacology Antiviral drugs antivirals Cell Line Competition Cytomegalovirus Drug Evaluation, Preclinical Hepacivirus - drug effects Hepatitis C Hepatitis C - drug therapy HIV Human immunodeficiency virus Humans medicinal chemistry Metabolism Metabolites nucleosides Nucleosides - chemical synthesis nucleotides Phosphates - chemistry Phosphoric Acids - chemistry prodrugs Prodrugs - chemical synthesis Prodrugs - pharmacology RNA polymerase Solvents Sulfur Thionucleosides - chemistry Viral Nonstructural Proteins - antagonists & inhibitors |
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| Title | Synthesis and Antiviral Activity of a Series of 2′-C-Methyl-4′-thionucleoside Monophosphate Prodrugs |
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