Solid-phase synthesis and screening of macrocyclic nucleotide-hybrid compounds targeted to hepatitis C NS5B.
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 microM. Preliminary structure-activity studies of this lead compound are described.
Smietana
Michael
M
Department of Chemistry, Stanford University, Stanford, CA 94305-5080, USA.
Johnson
Robert B
RB
Wang
Q May
QM
Kool
Eric T
ET
D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D002087:Butyrates / Q000378:metabolism; D003500:Cyclization; D004353:Drug Evaluation, Preclinical; D019384:Nucleic Acid Synthesis Inhibitors; D009712:Nucleotides, Cyclic / Q000737:chemistry; D009841:Oligonucleotides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D044367:Phase Transition; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors*; D012324:RNA-Dependent RNA Polymerase
D000998:Antiviral Agents; D002087:Butyrates; D019384:Nucleic Acid Synthesis Inhibitors; D009712:Nucleotides, Cyclic; D009841:Oligonucleotides; D012263:Ribonucleosides; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase; C011369:threonic acid