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Furan-Oxidation-Triggered Inducible DNA Cross-Linking: Acyclic Versus Cyclic Furan-Containing Building Blocks—On the Benefit of Restoring the Cyclic Sugar Backbone

Authors

  • Dr. Kristof Stevens,

    1. Laboratory for Organic and Biomimetic Chemistry, Department of Organic Chemistry, Ghent University, Krijgslaan 281, S4, 9000 Gent (Belgium), Fax: (+32) 9-264-49-98
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  • Dr. Diederica D. Claeys,

    1. Center for Molecular Modeling, Ghent University, Technologiepark 903, 9052 Zwijnaarde (Belgium)
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  • Dr. Saron Catak,

    1. Center for Molecular Modeling, Ghent University, Technologiepark 903, 9052 Zwijnaarde (Belgium)
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  • Sara Figaroli,

    1. Laboratory for Organic and Biomimetic Chemistry, Department of Organic Chemistry, Ghent University, Krijgslaan 281, S4, 9000 Gent (Belgium), Fax: (+32) 9-264-49-98
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  • Prof. Dr. Michal Hocek,

    1. Institute of Organic Chemistry and Biochemistry, Academy of Sciences of the Czech Republic, Gilead Sciences & IOCB Research Center, Flemingovo nam. 2, 16610 Prague 6 (Czech Republic)
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  • Dr. Jan M. Tromp,

    1. Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland)
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  • Prof. Dr. Stefan Schürch,

    1. Department of Chemistry and Biochemistry, University of Bern, Freiestrasse 3, 3012 Bern (Switzerland)
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  • Prof. Dr. Veronique Van Speybroeck,

    1. Center for Molecular Modeling, Ghent University, Technologiepark 903, 9052 Zwijnaarde (Belgium)
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  • Prof. Dr. Annemieke Madder

    Corresponding author
    1. Laboratory for Organic and Biomimetic Chemistry, Department of Organic Chemistry, Ghent University, Krijgslaan 281, S4, 9000 Gent (Belgium), Fax: (+32) 9-264-49-98
    • Laboratory for Organic and Biomimetic Chemistry, Department of Organic Chemistry, Ghent University, Krijgslaan 281, S4, 9000 Gent (Belgium), Fax: (+32) 9-264-49-98
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Abstract

Oligodeoxynucleotides incorporating a reactive functionality can cause irreversible cross-linking to the target sequence and have been widely studied for their potential in inhibition of gene expression or development of diagnostic probes for gene analysis. Reactive oligonucleotides further show potential in a supramolecular context for the construction of nanometer-sized DNA-based objects. Inspired by the cytochrome P450 catalyzed transformation of furan into a reactive enal species, we recently introduced a furan-oxidation-based methodology for cross-linking of nucleic acids. Previous experiments using a simple acyclic building block equipped with a furan moiety for incorporation into oligodeoxynucleotides have shown that cross-linking occurs in a very fast and efficient way and that substantial amounts of stable, site-selectively cross-linked species can be isolated. Given the destabilization of duplexes observed upon introduction of the initially designed furan-modified building block into DNA duplexes, we explore here the potential benefits of two new building blocks featuring an extended aromatic system and a restored cyclic backbone. Thorough experimental analysis of cross-linking reactions in a series of contexts, combined with theoretical calculations, permit structural characterization of the formed species and allow assessment of the origin of the enhanced cross-link selectivity. Our experiments clearly show that the modular nature of the furan-modified building blocks used in the current cross-linking strategy allow for fine tuning of both yield and selectivity of the interstrand cross-linking reaction.

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