Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues

K. C. Nicolaou, Shelby P. Ellery, Fatima Rivas, Karen Saye, Eric Rogers, Tyler J. Workinger, Mark Schallenberger, Rommel Tawatao, Ana Montero, Ann Hessell, Floyd Romesberg, Dennis Carson, Dennis Burton

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    10 Scopus citations

    Abstract

    Most nucleosides in solution typically exist in equilibrium between two major sugar pucker forms, N-type and S-type, but bridged nucleosides can be locked into one of these conformations depending on their specific structure. While many groups have researched these bridged nucleosides for the purpose of determining their binding affinity for antisense applications, we opted to look into the potential for biological activity within these conformationally-locked structures. A small library of 2′,4′- and 3′,4′-bridged nucleoside analogues was synthesized, including a novel 3′,4′- carbocyclic bridged system. The synthesized compounds were tested for antibacterial, antitumor, and antiviral activities, leading to the identification of nucleosides possessing such biological activities. To the best of our knowledge, these biologically active compounds represent the first example of 2′,4′-bridged nucleosides to demonstrate such properties. The most potent compound, nucleoside 33, exhibited significant antiviral activity against pseudoviruses SF162 (IC 50 = 7.0 μM) and HxB2 (IC 50 = 2.4 μM). These findings render bridged nucleosides as credible leads for drug discovery in the anti-HIV area of research.

    Original languageEnglish (US)
    Pages (from-to)5648-5669
    Number of pages22
    JournalBioorganic and Medicinal Chemistry
    Volume19
    Issue number18
    DOIs
    StatePublished - Sep 15 2011

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    Keywords

    • Antiviral
    • Cytotoxic
    • Nucleosides
    • Synthesis

    ASJC Scopus subject areas

    • Biochemistry
    • Molecular Medicine
    • Molecular Biology
    • Pharmaceutical Science
    • Drug Discovery
    • Clinical Biochemistry
    • Organic Chemistry

    Cite this

    Nicolaou, K. C., Ellery, S. P., Rivas, F., Saye, K., Rogers, E., Workinger, T. J., Schallenberger, M., Tawatao, R., Montero, A., Hessell, A., Romesberg, F., Carson, D., & Burton, D. (2011). Synthesis and biological evaluation of 2′,4′- and 3′,4′-bridged nucleoside analogues. Bioorganic and Medicinal Chemistry, 19(18), 5648-5669. https://doi.org/10.1016/j.bmc.2011.07.022