Structure-Dependent Binding of Arylimidamides to the DNA Minor Groove

Authors

  • Dr. Yun Chai,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Manoj Munde,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Arvind Kumar,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Leah Mickelson,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Sen Lin,

    1. The School of Pharmacy, University College London, 29–39 Brunswick Square, London WC1N 1 AX (UK)
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  • Dr. Nancy H. Campbell,

    1. The School of Pharmacy, University College London, 29–39 Brunswick Square, London WC1N 1 AX (UK)
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  • Dr. Moloy Banerjee,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Senol Akay,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Zongying Liu,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Abdelbasset A. Farahat,

    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
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  • Dr. Raja Nhili,

    1. INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team Molecular and Cellular Targeting for Cancer Treatment, Université Lille Nord de France, IMPRT-IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, 59045 Lille Cedex (France)
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  • Sabine Depauw,

    1. INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team Molecular and Cellular Targeting for Cancer Treatment, Université Lille Nord de France, IMPRT-IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, 59045 Lille Cedex (France)
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  • Prof. Marie-Hélène David-Cordonnier,

    1. INSERM U837-JPARC (Jean-Pierre Aubert Research Center), Team Molecular and Cellular Targeting for Cancer Treatment, Université Lille Nord de France, IMPRT-IFR-114, Institut pour la Recherche sur le Cancer de Lille, Place de Verdun, 59045 Lille Cedex (France)
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  • Prof. Stephen Neidle,

    1. The School of Pharmacy, University College London, 29–39 Brunswick Square, London WC1N 1 AX (UK)
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  • Prof. W. David Wilson,

    Corresponding author
    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
    • Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)===

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  • Prof. David W. Boykin

    Corresponding author
    1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)
    • Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA)===

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Abstract

Heterocyclic diamidines are strong DNA minor-groove binders and have excellent antiparasitic activity. To extend the biological activity of these compounds, a series of arylimidamides (AIAs) analogues, which have better uptake properties in Leishmania and Trypanosoma cruizi than diamidines, was prepared. The binding of the AIAs to DNA was investigated by Tm, fluorescence displacement titration, circular dichroism, DNase I footprinting, biosensor surface plasmon resonance, X-ray crystallography and molecular modeling. These compounds form 1:1 complexes with AT sequences in the DNA minor groove, and the binding strength varies with substituent size, charge and polarity. These substituent-dependent structure and properties provide a SAR that can be used to estimate K values for binding to DNA in this series. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for AIAs.

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