Synthesis and evaluation against hepatitis C virus of 7-deaza analogues of 2¡ä-C-methyl-6-O-methyl guanosine nucleoside and l-Alanine ester phosphoramidates

详细信息    查看全文

• 作者：Claire Bourdin^a ; Christopher McGuigan^a ; ^{mcguigan@cardiff.ac.uk} ; Andrea Brancale^a ; Stanley Chamberlain^b ; John Vernachio^b ; Jeff Hutchins^b ; Elena Gorovits^b ; Alexander Kolykhalov^b ; Jerry Muhammad^b ; Joseph Patti^b ; Geoffrey Henson^b ; Blair Bleiman^b ; K. Dawn Bryant^b ; Babita Ganguly^b ; Damound Hunley^b ; Aleksandr Obikhod^b ; C. Robin Walters^b ; Jin Wang^b ; Changalvala V.S. Ramamurty^b ; Srinivas K. Battina^b ; C. Srivinas Rao^c
• 关键词：HCV ; NS5b polymerase ; 2&prime ; -C-Methyl-6-O-methyl-7-deaza guanosine ; ProTide ; Phosphoramidate
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 April, 2013
• 年：2013
• 卷：23
• 期：7
• 页码：2260-2264
• 全文大小：641 K

文摘

7-Deazapurines are known to possess broad antiviral activity, however the 2¡ä-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¡ä-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¡ä-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¡ä-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¡ä-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.