2. Academic Validation
  3. Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2'-C-methyl-6-O-methyl guanosine nucleoside and L-Alanine ester phosphoramidates

Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2'-C-methyl-6-O-methyl guanosine nucleoside and L-Alanine ester phosphoramidates

  • Bioorg Med Chem Lett. 2013 Apr 1;23(7):2260-4. doi: 10.1016/j.bmcl.2012.12.004.
Claire Bourdin 1,  Christopher McGuigan,  Andrea Brancale,  Stanley Chamberlain,  John Vernachio,  Jeff Hutchins,  Elena Gorovits,  Alexander Kolykhalov,  Jerry Muhammad,  Joseph Patti,  Geoffrey Henson,  Blair Bleiman,  K Dawn Bryant,  Babita Ganguly,  Damound Hunley,  Aleksandr Obikhod,  C Robin Walters,  Jin Wang,  Changalvala V S Ramamurty,  Srinivas K Battina,  C Srivinas Rao
Affiliations

Affiliation

  • 1 School of Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
PMID: 23453067 DOI: 10.1016/j.bmcl.2012.12.004
Abstract

7-Deazapurines are known to possess broad Antiviral activity, however the 2'-C-methylguanosine analogue displays poor cell permeation and limited phosphorylation, thus is not an efficient inhibitor of hepatitis C virus (HCV) replication. We previously reported the 6-O-methyl entity as a prodrug moiety to increase liphophilicity of guanine nucleosides and the ProTide approach applied to 2'-C-methyl-6-O-methylguanosine has lead to potent HCV inhibitors now in clinical trials. In this Letter, we report the synthesis and biological evaluation of 2'-C-methyl-6-O-methyl-7-deaza guanosine and ProTide derivatives. In contrast to prior studies, removal of the N-7 of the nucleobase entirely negates anti-HCV activity compared to the 2'-C-methyl-6-O-methylguanosine analogues. To understand better this significant loss of activity, enzymatic assays and molecular modeling were carried out and suggested 2'-C-methyl-6-O-methyl-7-deaza guanosine and related ProTides do not act as efficient prodrugs of the free nucleotide, in marked contrast to the case of the parent guanine analogue.

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