Journal
CHEMBIOCHEM
Volume 15, Issue 1, Pages 68-79Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/cbic.201300622
Keywords
arylimidamides; DNA; minor-groove binders; molecular modeling; X-ray crystallography
Funding
- NIH [AI064200]
- Bill and Melinda Gates Foundation through Consortium of Parasitic Drug Development
- Cancer Research UK [C129/A4489]
- Fonds Europeen de Developpement Regional (FEDER, European Community)
- Region Nord-Pas de Calais
- Association Laurette Fugain
- Institut pour la Recherche sur le Cancer de Lille (IRCL)
- IRCL
- Ligue Nationale Contre le Cancer (Comite du Nord, Septentrion)
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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 T-m, 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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