- Synthesis and anti-viral activity of a series of D- and l-2′-deoxy-2′-fluororibonucleosides in the subgenomic HCV replicon system
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Based on the discovery of (2′R)-D-2′-deoxy-2′- fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of D- and L-2′-deoxy-2′-fluororibonucleosides with modifications at 5- and/or 4-positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The key step in the synthesis, the introduction of 2′-fluoro group, was achieved by either fluorination of 2,2′-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compound, namely (2′R)-D-2′-deoxy-2′,5-difluorocytidine (13), demonstrated potent anti-HCV activity and toxicity to ribosomal RNA. The replacement of the 4-amino group with a thiol group resulted in the loss of activity, while the 4-methylthio substituted analogue (25) exhibited inhibition of ribosomal RNA. As N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, we combined the two functionalities of the N4-hydroxyl and the 2′-fluoro into one molecule, resulting (2′R)-D-2′-deoxy- 2′-fluoro-N4-hydroxycytidine (23). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the L-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot always predict anti-HCV activity.
- Shi, Junxing,Du, Jinfa,Ma, Tianwei,Pankiewicz, Krzysztof W.,Patterson, Steven E.,Tharnish, Phillip M.,McBrayer, Tamara R.,Stuyver, Lieven J.,Otto, Michael J.,Chu, Chung K.,Schinazi, Raymond F.,Watanabe, Kyoichi A.
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p. 1641 - 1652
(2007/10/03)
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- Synthesis and in vitro anti-HCV activity of β-D- and L-2′-deoxy-2′-fluororibonucleosides
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Based on the discovery of β-D-2′-deoxy-2′-fluorocytidine as a potent anti-hepatitis C virus (HCV) agent, a series of β-D- and L-2′-deoxy-2′-fluororibonucleosides with modifications at 5 and/or 4 positions were synthesized and evaluated for their in vitro activity against HCV and bovine viral diarrhea virus (BVDV). The introduction of the 2′-fluoro group was achieved by either fluorination of 2,2′-anhydronucleosides with hydrogen fluoride-pyridine or potassium fluoride, or a fluorination of arabinonucleosides with DAST. Among the 27 analogues synthesized, only the 5-fluoro compounds, namely β-D-2′- deoxy-2′,5-difluorocytidine (5), had anti-HCV activity in the subgenomic HCV replicon cell line, and inhibitory activity against ribosomal RNA. As β-D-N4-hydroxycytidine (NHC) had previously shown potent anti-HCV activity, the two functionalities of the N4-hydroxyl and the 2′-fluoro were combined into one molecule, yielding β-D-2′- deoxy-2′-fluoro-N4-hydroxycytidine (12). However, this nucleoside showed neither anti-HCV activity nor toxicity. All the L-forms of the analogues were devoid of anti-HCV activity. None of the compounds showed anti-BVDV activity, suggesting that the BVDV system cannot reliably predict anti-HCV activity in vitro. Copyright Taylor & Francis, Inc.
- Shi, Junxing,Du, Jinfa,Ma, Tianwei,Pankiewicz, Krzysztof W.,Patterson, Steven E.,Hassan, Abdalla E. A.,Tharnish, Phillip M.,McBrayer, Tamara R.,Lostia, Stefania,Stuyver, Lieven J.,Watanabe, Kyoichi A.,Chu, Chung K.,Schinazi, Raymond F.,Otto, Michael J.
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p. 875 - 879
(2007/10/03)
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- Antisense modulation of Notch (Drosophila) homolog 4 expression
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Antisense compounds, compositions and methods are provided for modulating the expression of Notch (Drosophila) homolog 4. The compositions comprise antisense compounds, particularly antisense oligonucleotides, targeted to nucleic acids encoding Notch (Drosophila) homolog 4. Methods of using these compounds for modulation of Notch (Drosophila) homolog 4 expression and for treatment of diseases associated with expression of Notch (Drosophila) homolog 4 are provided.
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Page/Page column 16
(2010/02/06)
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- Synthesis and evaluation of thymidine-5′-O-monophosphate analogues as inhibitors of Mycobacterium tuberculosis thymidylate kinase
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A number of 2′- and 3′-modified thymidine 5′-O-monophosphate analogues were synthesized as potential leads for new anti-mycobacterial drugs. Evaluation of their affinity for Mycobacterium tuberculosis thymidine monophosphate kinase showed that a 2′-halogeno substituent and a 3′-azido function are the most favorable leads for further development of potent inhibitors of this enzyme.
- Vanheusden, Veerle,Munier-Lehmann, Helene,Pochet, Sylvie,Herdewijn, Piet,Van Calenbergh, Serge
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p. 2695 - 2698
(2007/10/03)
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