Design of DNA Minor Groove Binding Diamidines That Recognize GC Base Pair Sequences: A Dimeric-Hinge Interaction Motif

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• 作者：Manoj Munde ; Mohamed A. Ismail ; Reem Arafa ; Paul Peixoto ; Catharine J. Collar ; Yang Liu ; Laixing Hu ; Marie-H&eacute ; lè ; ne David-Cordonnier ; Am&eacute ; lie Lansiaux ; Christian Bailly ; David W. Boy
• 刊名：Journal of the American Chemical Society
• 出版年：2007
• 出版时间：November 7, 2007
• 年：2007
• 卷：129
• 期：44
• 页码：13732 - 13743
• 全文大小：629K
• 年卷期：v.129,no.44(November 7, 2007)
• ISSN：1520-5126

文摘

The classical model of DNA minor groove binding compounds is that they should have a crescentshape that closely fits the helical twist of the groove. Several compounds with relatively linear shape andlarge dihedral twist, however, have been found recently to bind strongly to the minor groove. Theseobservations raise the question of how far the curvature requirement could be relaxed. As an initial step inexperimental analysis of this question, a linear triphenyl diamidine, DB1111, and a series of nitrogen tricyclicanalogues were prepared. The goal with the heterocycles is to design GC binding selectivity into heterocycliccompounds that can get into cells and exert biological effects. The compounds have a zero radius ofcurvature from amidine carbon to amidine carbon but a significant dihedral twist across the tricyclic andamidine-ring junctions. They would not be expected to bind well to the DNA minor groove by shape-matchingcriteria. Detailed DNase I footprinting studies of the sequence specificity of this set of diamidines indicatedthat 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 minorgroove agents. Other similar derivatives did not exhibit the GC specificity. Biosensor-surface plasmonresonance and isothermal titration calorimetry experiments indicate that DB1242 binds to the GC sequenceas a highly cooperative stacked dimer. Circular dichroism results indicate that the compound binds in theminor groove. Molecular modeling studies support a minor groove complex and provide an inter-compoundand compound-DNA hydrogen-bonding rational for the unusual GC binding specificity and the requirementfor a pyrimidine heterocycle. This compound represents a new direction in the development of DNAsequence-specific agents, and it is the first non-polyamide, synthetic compound to specifically recognizea DNA sequence with a majority of GC base pairs.