Molecular recognition and physicochemical properties in the discovery of selective antibacterial minor groove binders

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Abstract

The polyamide minor groove binders (MGBs), distamycin and netropsin, have been known for many years to have significant biological activities but high toxicity. Strategies are described for the development of more selective MGBs taking advantage of hydrophobic interactions with the minor groove of DNA. The introduction of branched alkyl side chain substituents, planar aromatic head groups and alkene isosteres of the amides have all been investigated. MGBs designed using these strategies and built from heterocyclic and aromatic amino acids with the ability to recognise short sequences of DNA have been found to be potent and selective antibacterial agents. Detailed structural and strength of binding investigations (NMR, capillary electrophoresis (CE), DNA footprinting, melting temperature measurement, ITC) show that their activity depends primarily upon molecular recognition in terms of both molecular shape and specific hydrogen bonding. However the lack of toxicity depends upon their basic tail group structure, the pKa of which has a major influence on access to bacterial and mammalian cells. Lead compounds are active in vivo at doses competitive with recently introduced antibacterial drugs.
LanguageEnglish
Pages575-583
Number of pages8
JournalJournal of Physical Organic Chemistry
Volume21
Issue number7-8
DOIs
Publication statusPublished - Jul 2008

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Molecular recognition
grooves
Binders
Toxicity
deoxyribonucleic acid
DNA
Netropsin
toxicity
Lead compounds
Capillary electrophoresis
Aromatic Amino Acids
Nylons
Alkenes
Bioactivity
lead compounds
Amides
Temperature measurement
Melting point
Hydrogen bonds
Thermodynamic properties

Keywords

  • DNA binding
  • minor groove binder
  • molecular recognition
  • antibacterial compounds
  • pK(a)
  • log D

Cite this

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abstract = "The polyamide minor groove binders (MGBs), distamycin and netropsin, have been known for many years to have significant biological activities but high toxicity. Strategies are described for the development of more selective MGBs taking advantage of hydrophobic interactions with the minor groove of DNA. The introduction of branched alkyl side chain substituents, planar aromatic head groups and alkene isosteres of the amides have all been investigated. MGBs designed using these strategies and built from heterocyclic and aromatic amino acids with the ability to recognise short sequences of DNA have been found to be potent and selective antibacterial agents. Detailed structural and strength of binding investigations (NMR, capillary electrophoresis (CE), DNA footprinting, melting temperature measurement, ITC) show that their activity depends primarily upon molecular recognition in terms of both molecular shape and specific hydrogen bonding. However the lack of toxicity depends upon their basic tail group structure, the pKa of which has a major influence on access to bacterial and mammalian cells. Lead compounds are active in vivo at doses competitive with recently introduced antibacterial drugs.",
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N2 - The polyamide minor groove binders (MGBs), distamycin and netropsin, have been known for many years to have significant biological activities but high toxicity. Strategies are described for the development of more selective MGBs taking advantage of hydrophobic interactions with the minor groove of DNA. The introduction of branched alkyl side chain substituents, planar aromatic head groups and alkene isosteres of the amides have all been investigated. MGBs designed using these strategies and built from heterocyclic and aromatic amino acids with the ability to recognise short sequences of DNA have been found to be potent and selective antibacterial agents. Detailed structural and strength of binding investigations (NMR, capillary electrophoresis (CE), DNA footprinting, melting temperature measurement, ITC) show that their activity depends primarily upon molecular recognition in terms of both molecular shape and specific hydrogen bonding. However the lack of toxicity depends upon their basic tail group structure, the pKa of which has a major influence on access to bacterial and mammalian cells. Lead compounds are active in vivo at doses competitive with recently introduced antibacterial drugs.

AB - The polyamide minor groove binders (MGBs), distamycin and netropsin, have been known for many years to have significant biological activities but high toxicity. Strategies are described for the development of more selective MGBs taking advantage of hydrophobic interactions with the minor groove of DNA. The introduction of branched alkyl side chain substituents, planar aromatic head groups and alkene isosteres of the amides have all been investigated. MGBs designed using these strategies and built from heterocyclic and aromatic amino acids with the ability to recognise short sequences of DNA have been found to be potent and selective antibacterial agents. Detailed structural and strength of binding investigations (NMR, capillary electrophoresis (CE), DNA footprinting, melting temperature measurement, ITC) show that their activity depends primarily upon molecular recognition in terms of both molecular shape and specific hydrogen bonding. However the lack of toxicity depends upon their basic tail group structure, the pKa of which has a major influence on access to bacterial and mammalian cells. Lead compounds are active in vivo at doses competitive with recently introduced antibacterial drugs.

KW - DNA binding

KW - minor groove binder

KW - molecular recognition

KW - antibacterial compounds

KW - pK(a)

KW - log D

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