Synthesis and Biological Evaluation of 5'-C-Methyl Nucleotide Prodrugs for Treating HCV Infections.

Synthesis and Biological Evaluation of 5'-C-Methyl Nucleotide Prodrugs for Treating HCV Infections. Bioorg Med Chem Lett. 2020 Sep 09;:127539 Authors: Dasari M, Ma P, Pelly SC, Sharma SK, Liotta DC Abstract Nucleotide prodrugs are of great clinical interest for treating a variety of viral infections due to their ability to target tissues selectively and to deliver relatively high concentrations of the active nucleotide metabolite intracellularly. However, their clinical successes have been limited, oftentimes due to unwanted in vivo metabolic processes that reduce the quantities of nucleoside triphosphate that reach the site of action. In an attempt to circumvent this, we designed novel nucleosides that incorporate a sterically bulky group at the 5'-carbon of the phosphoester prodrug, which we reasoned would reduce the amounts of non-productive P-O bond cleavage back to the corresponding nucleoside by nucleotidases. Molecular docking studies with the NS5B HCV polymerase suggested that a nucleotide containing a 5'-methyl group could be accommodated. Therefore, we synthesized mono- and diphosphate prodrugs of 2',5'-C-dimethyluridine stereoselectively and evaluated their cytotoxicity and anti-HCV activity in the HCV replicon assay. All four prodrugs exhibited anti-HCV activity with IC50 values in the single digit micromolar concentrations, with the 5'(R)-C-methyl prodrug displaying superior potency relative to its 5'(S)-C-methyl counter...
Source: Bioorganic and Medicinal Chemistry Letters - Category: Chemistry Authors: Tags: Bioorg Med Chem Lett Source Type: research