2 research outputs found
Synthesis of (2<i>S</i>)‑2-Chloro-2-fluororibolactone via Stereoselective Electrophilic Fluorination
A novel and efficient route for the
preparation of (2<i>S</i>)-2-chloro-2-fluorolactone <b>29</b> is described. This approach
takes advantage of a highly efficient diastereoselective electrophilic
fluorination reaction (94% yield; >50:1 dr
2′-Chloro,2′-fluoro Ribonucleotide Prodrugs with Potent Pan-genotypic Activity against Hepatitis C Virus Replication in Culture
Pan-genotypic
nucleoside HCV inhibitors display a high genetic
barrier to drug resistance and are the preferred direct-acting agents
to achieve complete sustained virologic response in humans. Herein,
we report, the discovery of a β-d-2′-Cl,2′-F-uridine
phosphoramidate nucleotide <b>16</b>, as a nontoxic pan-genotypic
anti-HCV agent. Phosphoramidate <b>16</b> in its 5′-triphosphate
form specifically inhibited HCV NS5B polymerase with no marked inhibition
of human polymerases and cellular mitochondrial RNA polymerase. Studies
on the intracellular half-life of phosphoramidate <b>16</b>-TP
in live cells demonstrated favorable half-life of 11.6 h, suggesting
once-a-day dosing. Stability in human blood and favorable metabolism
in human intestinal microsomes and liver microsomes make phosphoramidate <b>16</b> a prospective candidate for further studies to establish
its potential value as a new anti-HCV agent