Structure‐Dependent Binding of Arylimidamides to the DNA Minor Groove |
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| Authors: | Dr Yun Chai Dr Manoj Munde Dr Arvind Kumar Leah Mickelson Dr Sen Lin Dr Nancy H Campbell Dr Moloy Banerjee Dr Senol Akay Dr Zongying Liu Dr Abdelbasset A Farahat Dr Raja Nhili Sabine Depauw Prof Marie‐Hélène David‐Cordonnier Prof Stephen Neidle Prof W David Wilson Prof David W Boykin |
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| Affiliation: | 1. Department of Chemistry, Georgia State University, 50 Decatur St. SE., Atlanta, GA 30303 (USA);2. The School of Pharmacy, University College London, 29–39 Brunswick Square, London WC1N 1 AX (UK);3. 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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| 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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| Keywords: | arylimidamides DNA minor‐groove binders molecular modeling X‐ray crystallography |
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