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Solid‐Phase Synthesis and Screening of Macrocyclic Nucleotide‐Hybrid Compounds Targeted to Hepatitis C NS5B
Author(s) -
Smietana Michael,
Johnson Robert B.,
Wang Q. May,
Kool Eric T.
Publication year - 2004
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200305402
Subject(s) - ns5b , nucleotide , chemistry , stereochemistry , phosphoramidite , combinatorial chemistry , hepatitis c virus , dna , oligonucleotide , virology , hepacivirus , biology , biochemistry , virus , gene
A convergent strategy for the synthesis of cyclic nucleotide‐hybrid molecules on controlled pore glass is reported. A major advantage of the approach is the lack of restrictions on the sequence and structural variation, allowing the incorporation of modified ribonucleosides (such as 2′‐OMe‐ribonucleotides), as well as threoninol derivatives. This methodology allows a fully automated assembly by means of standard phosphoramidite chemistry and is based on a recently published procedure for the preparation of cyclic oligodinucleotides in the DNA series (M. Smietana, E. T. Kool, Angew . Chem . 2002 , 114 , 3856–3859; Angew . Chem . Int . Ed . Engl . 2002 , 41 , 3704–3707). A library of potential cyclic hybrid inhibitor compounds targeting hepatitis C virus NS5B enzyme (the replicating polymerase of HCV) was generated by means of the parallel‐pool strategy. Screening of the library revealed that cyclic hybrid c (C OME EthenodA) was a significant inhibitor of NS5B, with an IC 50 of 40 μ M . Preliminary structure–activity studies of this lead compound are described.