Concise syntheses and HCV NS5B polymerase inhibition of (2'R)-3 and (2'S)-2'-ethynyluridine-10 and related nucleosides.

Bioorganic & medicinal chemistry letters 2017 Dec 01

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2'R)-Ethynyl uridine 3, and its (2'S)-diastereomer 10, are synthesised in a divergent fashion from the inexpensive parent nucleoside. Both nucleoside analogues are obtained from a total of 5 simple synthetic steps and 3 trivial column chromatography purifications. To evaluate their effectiveness against HCV NS5B polymerase, the nucleosides were converted to their respective 5'-O-triphosphates. Subsequently, this lead to the discovery of the 2'-β-ethynyl 18 and -propynyl 20 nucleotides having significantly improved potency over Sofosbuvir triphosphate 24. Copyright © 2017 Elsevier Ltd. All rights reserved.

Citation

Frank Bennett, Alexei V Buevich, Hsueh-Cheng Huang, Vinay Girijavallabhan, Angela D Kerekes, Yuhua Huang, Asra Malikzay, Elizabeth Smith, Eric Ferrari, Mary Senior, Rebecca Osterman, Lingyan Wang, Jun Wang, Haiyan Pu, Quang T Truong, Paul Tawa, Stephane L Bogen, Ian W Davies, Ann E Weber. Concise syntheses and HCV NS5B polymerase inhibition of (2'R)-3 and (2'S)-2'-ethynyluridine-10 and related nucleosides. Bioorganic & medicinal chemistry letters. 2017 Dec 01;27(23):5349-5352