DNA minor-groove recognition by small molecules (up to 2000)

Neidle, Stephen

doi:10.1039/a705982e

Cited by 469 publications

(398 citation statements)

References 225 publications

(158 reference statements)

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“…Hydrogen bond donating groups on the concave face of these compounds contact hydrogen bond acceptors on the A and T base edges that are exposed at the floor of the groove in the -AATT-site. 9 The minor groove width in AT sequences can narrow to the width of the unfused aromatic groups in the compounds without a large energy penalty 41,50 and the compounds make extensive energetically favorable contacts with the walls of the minor groove. The positive charges on the amidines or other groups provide electrostatic contributions to the complex energetics through phosphate interactions.…”

Section: Discussionmentioning

confidence: 99%

“…Diamidines have excellent transport properties into a variety of cells [3][4][5][6] and an orally available prodrug of the diamidine, DB75, furamidine (Figure 1), is currently in phase III clinical trials against trypanosomes, which cause sleeping sickness, as well as other microbial parasites. 4,[7][8][9][10][11] DB75 binds strongly in the minor groove of DNA and recognizes sequences of at least four AT base pairs. [7][8][9] For design of new agents that target additional disease organisms/cells as well as evading any possible resistance that could develop, we have focused on modifications of the structure, heterocycles, and properties of the basic units of the DB75 molecule.…”

Section: Introductionmentioning

confidence: 99%

“…4,[7][8][9][10][11] DB75 binds strongly in the minor groove of DNA and recognizes sequences of at least four AT base pairs. [7][8][9] For design of new agents that target additional disease organisms/cells as well as evading any possible resistance that could develop, we have focused on modifications of the structure, heterocycles, and properties of the basic units of the DB75 molecule. A key aim of the design considerations was to discover motifs that could expand the sequence recognition properties of diamidines by including a variety of nitrogen heterocycles into molecules of different shape.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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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 DNaseI footprinting studies of the sequence specificity of this set of diamidines indicated that a pyrimidine heterocyclic derivative, DB1242, has remarkable binding specificity for 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 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2007

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“…14,27 These observations suggest that the wide minor groove of canonical G/C-regions leads to a less efficient metallopeptide interaction, as typically observed with other minor groove binding agents. 28 Perhaps the width of the minor groove at mixed A/T-regions, and other minor groove nucleotide compositions that resemble this width, are neither too wide nor too narrow, steering the metallopeptide catalyst in such a way as to optimize access to the C4′-H target; correct groove width may also serve to optimize residence time of the DNA-associated metallopeptide "catalyst", leading to a greater relative observed reactivity.…”

Section: Discussionmentioning

confidence: 99%

Diastereoselective DNA Cleavage Recognition by Ni(II)•Gly-Gly-His-Derived Metallopeptides

et al. 2006

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Site-selective DNA cleavage by diastereoisomers of Ni(II)•Gly-Gly-His-derived metallopeptides was investigated through high-resolution gel analyses and molecular dynamics simulations. Ni(II) •L-Arg-Gly-His and Ni(II)•D-Arg-Gly-His (and their respective Lys analogues) targeted A/T-rich regions; however, the L-isomers consistently modified a sub-set of available nucleotides within a given minor groove site while the D-isomers differed in both their sites of preference and ability to target individual nucleotides within some sites. In comparison, Ni(II)•L-Pro-Gly-His and Ni(II)•DPro-Gly-His were unable to exhibit a similar diastereoselectivity. Simulations of the above systems, along with Ni(II)•Gly-Gly-His, indicated that the stereochemistry of the amino-terminal amino acid produces either an isohelical metallopeptide that associates stably at individual DNA sites (L-Arg or L-Lys) or, with D-Arg and D-Lys, a non-complementary metallopeptide structure that cannot fully employ its side chain nor amino-terminal amine as a positional stabilizing moiety. In contrast, aminoterminal Pro-containing metallopeptides of either stereochemistry, lacking an extended side chain directed toward the minor groove, did not exhibit a similar diastereoselectivity. While the identity and stereochemistry of amino acids located in the amino-terminal peptide position influenced DNA cleavage, metallopeptide diastereoisomers containing L-and D-Arg (or Lys) within the second peptide position did not exhibit diastereoselective DNA cleavage patterns; simulations indicated that a positively-charged amino acid in this location alters the interaction of the metallopeptide equatorial plane and the minor groove leading to an interaction similar to Ni(II)•Gly-Gly-His.

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“…Early studies of netropsin binding to synthetic polydeoxyribonucleotides by Zimmer and coworkers [6,7] revealed sequence dependent differences in affinities and complex structures. The weak binding of the minor groove-targeted compounds listed above to GC containing sites has been explained by structural studies which show the compounds bound deep in the minor groove in AT sites and in close contact with the edges of AT base pairs at the floor of the groove [8][9][10][11][12]. This allows H-bonds to form with the TO2 and AN3 groups in AT base pairs but such close contact is sterically prevented by the 2-NH 2 group of G. The diversity of affinities for minor groove compounds with AT sequences, however, has not been extensively investigated.…”

Section: Introductionmentioning

confidence: 99%

Sequence and length dependent thermodynamic differences in heterocyclic diamidine interactions at AT base pairs in the DNA minor groove

Liu

Kumar

Boykin

et al. 2007

Biophysical Chemistry

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With the goal of developing a better understanding of the antiparasitic biological action of DB75, we have evaluated its interaction with duplex alternating and nonalternating sequence AT polymers and oligomers. These DNAs provide an important pair of sequences in a detailed thermodynamic analysis of variations in interaction of DB75 with AT sites. The results for DB75 binding to the alternating and nonalternating AT sequences are quite different at the fundamental thermodynamic level. Although the Gibbs energies are similar, the enthalpies for DB75 binding with poly(dA)·poly (dT) and poly(dA-dT)·poly(dA-dT) are +3.1 and −4.5 kcal/mole, respectively, while the binding entropies are 41.7 and 15.2 cal/mol·K, respectively. The underlying thermodynamics of binding to AT sites in the minor groove plays a key role in the recognition process. It was also observed that DB75 binding with poly(dA)·poly(dT) can induce T·A·T triplet formation and the compound binds strongly to the dT·dA·dT triplex.

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DNA minor-groove recognition by small molecules (up to 2000)

Cited by 469 publications

References 225 publications

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

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

Diastereoselective DNA Cleavage Recognition by Ni(II)•Gly-Gly-His-Derived Metallopeptides

Sequence and length dependent thermodynamic differences in heterocyclic diamidine interactions at AT base pairs in the DNA minor groove

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