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

Bourdin, Claire, McGuigan, Christopher ORCID: https://orcid.org/0000-0001-8409-710X, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419, 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. and Rao, C.Srivinas 2013. 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. Biorganic & Medicinal Chemistry Letters 23 (7) , pp. 2260-2264. 10.1016/j.bmcl.2012.12.004

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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 paper, 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.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Pharmacy Systems Immunity Research Institute (SIURI)
Subjects:	Q Science > QR Microbiology > QR180 Immunology R Medicine > RM Therapeutics. Pharmacology
Uncontrolled Keywords:	HCV; NS5b polymerase; 2’-C-methyl-6-O-methyl-7-deaza guanosine; ProTide; Phosphoramidate
Publisher:	Elsevier
ISSN:	0960-894X
Last Modified:	05 Jan 2024 05:53
URI:	https://orca.cardiff.ac.uk/id/eprint/43410

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