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
  • 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.