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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Design of DNA minor groove binding diamidines that recognize GC base pair sequences: A dimeric-hinge interaction motif
Journal of the American Chemical Society, Volume 129, No. 44, Year 2007
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Description
The classical model of DNA minor groove binding compounds is that they should have a crescent shape that closely fits the helical twist of the groove. Several compounds with relatively linear shape and large dihedral twist, however, have been found recently to bind strongly to the minor groove. These observations raise the question of how far the curvature requirement could be relaxed. As an initial step in experimental analysis of this question, a linear triphenyl diamidine, DB1111, and a series of nitrogen tricyclic analogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocyclic compounds that can get into cells and exert biological effects. The compounds have a zero radius of curvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic and amidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matching criteria. Detailed DNase I footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, binds specifically to a GC-rich sequence, -GCTCG-. It binds to the GC sequence more strongly than to the usual AT recognition sequences for curved minor groove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmon resonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequence as a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in the minor groove. Molecular modeling studies support a minor groove complex and provide an inter-compound and compound-DNA hydrogen-bonding rational for the unusual GC binding specificity and the requirement for a pyrimidine heterocycle. This compound represents a new direction in the development of DNA sequence-specific agents, and it is the first non-polyamide, synthetic compound to specifically recognize a DNA sequence with a majority of GC base pairs. © 2007 American Chemical Society.
Authors & Co-Authors
Munde, Manoj M.
United States, Atlanta
Georgia State University
Ismail, Mohamed A.
United States, Atlanta
Georgia State University
Arafa, Reem K.
United States, Atlanta
Georgia State University
Peixoto, Paul
Unknown Affiliation
Liu, Yang
United States, Atlanta
Georgia State University
Hu, Laixing
United States, Atlanta
Georgia State University
David-Cordonnier, Marie Hélène
Unknown Affiliation
Lansiaux, Amélie
France, Lille
Centre Oscar Lambret
Bailly, Christian
France, Castres
Pierre Fabre Recherche et Devéloppement
Boykin, David Withers
United States, Atlanta
Georgia State University
Wilson, W. David
United States, Atlanta
Georgia State University
Statistics
Citations: 63
Authors: 11
Affiliations: 3
Identifiers
Doi:
10.1021/ja074560a
ISSN:
00027863
Research Areas
Cancer
Environmental
Genetics And Genomics
Study Design
Case-Control Study