Synthesis and Antiviral Activity of a Series of 2′-C-Methyl-4′-thionucleoside Monophosphate Prodrugs

• Published in: Molecules (Basel, Switzerland) Vol. 25; no. 21; p. 5165
• Main Authors: Dentmon, Zackery W., Kaiser, Thomas M., Liotta, Dennis C.
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 06.11.2020; MDPI
• Subjects: 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; antivirals; nucleosides; prodrugs; nucleotides; hepatitis C; medicinal chemistry
• ISSN: 1420-3049; 1420-3049
• DOI: 10.3390/molecules25215165

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.