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

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 moie...

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Bibliographic Details
Published in:	Bioorganic & medicinal chemistry letters Vol. 23; no. 7; pp. 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:	Journal Article
Language:	English
Published:	England Elsevier Ltd 01-04-2013
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 HCV 2′-C-Methyl-6-O-methyl-7-deaza guanosine Phosphoramidate NS5b polymerase ProTide
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Summary:	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.
Bibliography:	http://dx.doi.org/10.1016/j.bmcl.2012.12.004 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	0960-894X 1464-3405
DOI:	10.1016/j.bmcl.2012.12.004