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

• Published in: Bioorganic & medicinal chemistry letters 2013-04, Vol.23 (7), p.2260-2264
• Main Authors: Bourdin, Claire, McGuigan, Christopher, Brancale, Andrea, Chamberlain, Stanley, Vernachio, John, Hutchins, Jeff, Gorovits, Elena, Kolykhalov, Alexander, Muhammad, Jerry, Patti, Joseph, Henson, Geoffrey, Bleiman, Blair, Bryant, K. Dawn, Ganguly, Babita, Hunley, Damound, Obikhod, Aleksandr, Walters, C. Robin, Wang, Jin, Ramamurty, Changalvala V.S., Battina, Srinivas K., Srivinas Rao, C.
• Format: Article
• Language: English
• Subjects: 2′-C-Methyl-6-O-methyl-7-deaza guanosine; alanine; Alanine - chemistry; Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; antiviral properties; clinical trials; Esters - chemical synthesis; Esters - chemistry; Esters - pharmacology; guanine; Guanine - analogs & derivatives; Guanine - chemical synthesis; Guanine - chemistry; Guanine - pharmacology; guanosine; HCV; Hepacivirus - drug effects; Hepatitis C virus; Microbial Sensitivity Tests; Models, Molecular; Molecular Structure; NS5b polymerase; Phosphoramidate; Phosphoric Acids - chemical synthesis; Phosphoric Acids - chemistry; Phosphoric Acids - pharmacology; phosphorylation; ProTide
• ISSN: 0960-894X; 1464-3405
• DOI: 10.1016/j.bmcl.2012.12.004

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.