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Issue 11, 2015
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Bisimidazoline arylamides binding to the DNA minor groove: N1-hydroxylation enhances binding affinity and selectivity to AATT sites

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Abstract

Bisimidazoline arylamides and related compounds are high affinity DNA minor groove binders with a preference for AT over GC-rich DNA. However, further selectivity towards different classes of AT-sites (e.g., CGAATTCG, CATATATAT) is not always observed with these series. In this work, we wanted to understand the effect of imidazoline ring N-substitution on binding to DNA AT-sites. The structure–affinity relationships of a series of structurally related bisimidazoline compounds were studied by UV titrations and surface plasmon resonance (SPR) experiments using fish sperm DNA and different hairpin oligonucleotides. We found that in this series, the presence of N1–OH groups enhances the binding affinity to dsDNA CGAATTCG oligonucleotide, resulting in a higher selectivity for dsDNA containing AATT over (AT)4 sequences. The docking models showed that the N-hydroxy derivatives bind in a more planar conformation to the CGAATTCG DNA sequence, display more favorable van der Waals interactions, and show additional H-bonds with the bases and the sugar-phosphate backbone.

Graphical abstract: Bisimidazoline arylamides binding to the DNA minor groove: N1-hydroxylation enhances binding affinity and selectivity to AATT sites

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Publication details

The article was received on 09 Jul 2015, accepted on 05 Oct 2015 and first published on 08 Oct 2015


Article type: Concise Article
DOI: 10.1039/C5MD00292C
Citation: Med. Chem. Commun., 2015,6, 2036-2042
  • Open access: Creative Commons BY-NC license
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    Bisimidazoline arylamides binding to the DNA minor groove: N1-hydroxylation enhances binding affinity and selectivity to AATT sites

    C. H. Ríos Martínez, L. Lagartera, C. Trujillo and C. Dardonville, Med. Chem. Commun., 2015, 6, 2036
    DOI: 10.1039/C5MD00292C

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