Use of 2鈥?Spirocyclic Ethers in HCV Nucleoside Design

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• 作者：Jinfa Du ; Byoung-Kwon Chun ; Ralph T. Mosley ; Shalini Bansal ; Haiying Bao ; Christine Espiritu ; Angela M. Lam ; Eisuke Murakami ; Congrong Niu ; Holly M. Micolochick Steuer ; Phillip A. Furman ; Michael J. Sofia
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：March 13, 2014
• 年：2014
• 卷：57
• 期：5
• 页码：1826-1835
• 全文大小：451K
• 年卷期：v.57,no.5(March 13, 2014)
• ISSN：1520-4804

文摘

Conformationally restricted 2鈥?spironucleosides and their prodrugs were synthesized as potential anti-HCV agents. Although the replicon activity of the new agents containing pyrimidine bases was modest, the triphosphate of a 2鈥?oxetane cytidine analogue demonstrated potent intrinsic biochemical activity against the NS5B polymerase, with IC₅₀ = 8.48 渭M. Activity against NS5B bearing the S282T mutation was reduced. Phosphoramidate prodrugs of a 2鈥?oxetane 2-amino-6-O-methyl-purine nucleoside demonstrated potent anti-HCV activity in vitro, and the corresponding triphosphate retained similar potent activity against both wild-type and S282T HCV NS5B polymerase.