Asymmetric Synthesis of 2'-C -Methyl-4'-selenonucleosides as Anti-Hepatitis C Virus Agents.

Journal Article (Journal Article)

In search of a new template for anti-hepatitis C virus (HCV) agents, we designed and synthesized the 2'-C -methyl-4'-selenopyrimidine and -purine nucleosides and their phosphoramidate prodrugs to replace a furanose oxygen of anti-HCV nucleos(t)ides with a selenium atom on the basis that selenium is a chemical isostere of oxygen. These nucleosides are expected to show different physicochemical properties such as better lipophilicity which might enhance the penetration across cell membranes and the conformational constraint induced by a bulky selenium atom in the sugar ring. The 2'-C -methyl-4'-selenopyrimidine and -purine nucleosides 8 and 9 were synthesized from 2-C -methyl-d-ribono-γ-lactone (14 ) via construction of 2-C -methyl-d-selenosugar 18 through C -4 epimerization and SN 2 cyclization with Se2- as key steps. The key 4'-selenosugar was converted to the 2'-C -methyl-4'-selenopyrimidine and -purine nucleosides using Pummerer-type rearrangement and Vorbrüggen glycosylation, respectively. In addition, the ProTide strategy has been applied to synthesize the adenine and uracil phosphoramidate derivatives 10a and 10b to overcome the limitations associated with parent nucleosides such as inefficient conversion to their corresponding 5'-monophosphate form and poor cellular uptake. The regio- and stereochemistry of 4'-selenonucleosides were confirmed by 2D NOESY NMR spectroscopy and X-ray crystallography. None of the final pyrimidine and purine nucleosides and their prodrugs exhibited significant anti-HCV activity up to 100 μM.

Full Text

Duke Authors

Cited Authors

  • Lee, H; Jarhad, DB; Yu, J; Lee, C; Jeong, LS

Published Date

  • November 2019

Published In

Volume / Issue

  • 84 / 22

Start / End Page

  • 14414 - 14426

PubMed ID

  • 31608633

Electronic International Standard Serial Number (EISSN)

  • 1520-6904

International Standard Serial Number (ISSN)

  • 0022-3263

Digital Object Identifier (DOI)

  • 10.1021/acs.joc.9b01462

Language

  • eng