Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Tidwell, Richard R.; Boykin, David W.

doi:10.1002/3527601783.ch16

Cited by 80 publications

(166 citation statements)

References 123 publications

(254 reference statements)

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“…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: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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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“…As described above, the diamidines are attractive for development due to their demonstrated low toxicity in humans, extensive clinical testing and cell uptake properties. 1,2,14,15 In order to accomplish the drug development and molecular recognition goals, a variety of dications, such as those shown in Figure 1, are being designed and prepared. The synthetic compounds are screened by footprinting and Tm methods to select for structures that can selectively target DNA with high affinity.…”

Section: Introductionmentioning

confidence: 99%

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

et al. 2007

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To better understand the molecular basis for recognition of the DNA minor groove by heterocyclic cations, a series of "reversed amidine" substituted heterocycles has been prepared. Amidine derivatives for targeting the minor groove have the amidine carbon linked to a central heterocyclic system while in the reverse orientation, an amidine nitrogen provides the link. The reverse system has a larger dihedral angle as well as a modified spatial relationship with the groove relative to amidines. Because of the large dihedral, the reversed amidines should have reduced binding to DNA relative to similar amidines. Such a reduction is observed in footprinting, circular dichroism (CD), biosensor-surface plasmon resonance (SPR) and isothermal titration calorimetric (ITC) experiments with DB613, which has a central phenyl-furan-phenyl heterocyclic system. The reduction is not seen when a pyrrole (DB884) is substituted for the furan. Analysis of a number of derivatives defines the pyrrole and a terminal phenyl substituent on the reversed amidine groups as critical components in the strong binding of DB884. ITC and SPR comparisons showed that the better binding of DB884 was due to a more favorable binding enthalpy and that it had exceptionally slow dissociation from DNA. Crystallographic analysis of DB884 bound to an AATT site show that the compound was bound in the minor groove in a 1:1 complex as suggested by CD solution studies. Surprisingly, unlike the amidine derivative, the pyrrole -NH of DB884 formed an H-bond with a central T of the AATT site and this accounts for the enthalpy driven strong binding. The structural results and molecular modeling studies provide an explanation for the differences in binding affinities for related amidine and reversed amidine analogs.

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“…[1][2][3][4] Furamidine (2) is the parent compound of this class, and it's methoxime prodrug (3) (Pafuramidine) is currently in clinical trials for treatment of African Sleeping sickness, malaria, and pneumocystis carinii pneumonia. [4][5] Satisfactory methods for conversion of the intermediate bis-nitrile 1 to 2 and 3 are available. 1,6 Several methods for the synthesis of bis-nitrile 1 are also available; 6-8 however many of these methods require multiple steps and/or are not high yielding.…”

Section: Introductionmentioning

confidence: 99%

A new synthesis of 2,5-bis(4-cyanophenyl)furan

Suthiwangcharoen¹,

Stephens²

2007

Arkivoc

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A new 3-step synthesis of 2,5-bis(4-cyanophenyl)furan, a key intermediate in the preparation of the antimicrobial agents Furamidine and Pafuramidine, is presented. The key step of the synthesis is the preparation of a 1,4-diketone via the modified Stetter reaction of a 4-cyanophenyl Mannich base as a vinyl ketone precursor with 4-cyanobenzaldehyde. The synthesis has potential for use in the large scale preparation of the two antimicrobial agents.

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Dicationic DNA Minor Groove Binders as Antimicrobial Agents

Cited by 80 publications

References 123 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

Induced Fit Conformational Changes of a “Reversed Amidine” Heterocycle: Optimized Interactions in a DNA Minor Groove Complex

A new synthesis of 2,5-bis(4-cyanophenyl)furan

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