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.
Highlights
Scientists have long been interested in the medicinal applications of non-canonical nucleosides and nucleotides due to their privileged bioactivity
Sofosbuvir bears the hepatic-directing iodo-2′-deoxyuridine, see Figure 1a, modified nucleosides and nucleotides have found use ProTide monophosphate prodrug moiety pioneered by Christopher McGuigan and co-workers predominantly as anti-neoplastics and antivirals for their ability to inhibit nucleic acid at Cardiff University [12,13]
3′-azidothymidine (AZT), the first approved which is known to be a culprit of poor anabolism and low levels of NTP [16,17,18]. It stands to reason treatment against human immunodeficiency virus (HIV), appears on this list along with a dozen that these two structural features (20 -β-methyl and 50 -phosphoramidate prodrug moieties) would other nucleos(t)ide analogs acting as antivirals alone [2,3,4]
Summary
Scientists have long been interested in the medicinal applications of non-canonical nucleosides and nucleotides due to their privileged bioactivity. Sofosbuvir bears the hepatic-directing iodo-2′-deoxyuridine, see Figure 1a, modified nucleosides and nucleotides have found use ProTide monophosphate prodrug moiety pioneered by Christopher McGuigan and co-workers predominantly as anti-neoplastics and antivirals for their ability to inhibit nucleic acid at Cardiff University [12,13] Their lab has utilized ProTide technology to turn inactive parent polymerization and replication by competing with nucleoside triphosphates (NTPs), the natural nucleosides into sub-micromolar inhibitors of HCV replicons [14,15]. 3′-azidothymidine (AZT), the first approved which is known to be a culprit of poor anabolism and low levels of NTP [16,17,18] It stands to reason treatment against human immunodeficiency virus (HIV), appears on this list along with a dozen that these two structural features (20 -β-methyl and 50 -phosphoramidate prodrug moieties) would other nucleos(t)ide analogs acting as antivirals alone [2,3,4]. Compositions, and (b) historical 4′-thionucleoside analogs having notable bioactivity
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