title: 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.
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.
authors: School of Pharmaceutical Sciences, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK.
authors: Claire
authors: C
authors: Bourdin
authors: Christopher
authors: C
authors: McGuigan
authors: Andrea
authors: A
authors: Brancale
authors: Stanley
authors: S
authors: Chamberlain
authors: John
authors: J
authors: Vernachio
authors: Jeff
authors: J
authors: Hutchins
authors: Elena
authors: E
authors: Gorovits
authors: Alexander
authors: A
authors: Kolykhalov
authors: Jerry
authors: J
authors: Muhammad
authors: Joseph
authors: J
authors: Patti
authors: Geoffrey
authors: G
authors: Henson
authors: Blair
authors: B
authors: Bleiman
authors: K Dawn
authors: KD
authors: Bryant
authors: Babita
authors: B
authors: Ganguly
authors: Damound
authors: D
authors: Hunley
authors: Aleksandr
authors: A
authors: Obikhod
authors: C Robin
authors: CR
authors: Walters
authors: Jin
authors: J
authors: Wang
authors: Changalvala V S
authors: CV
authors: Ramamurty
authors: Srinivas K
authors: SK
authors: Battina
authors: C
authors: C
authors: Srivinas Rao
mesh_terms: D000409:Alanine / Q000737:chemistry*; D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004952:Esters / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000577:Amides; D000998:Antiviral Agents; D004952:Esters; D010756:Phosphoric Acids; D006147:Guanine; C011067:phosphoramidic acid; C066856:7-deazaguanine; D000409:Alanine