Structure, DNA Minor Groove Binding, and Base Pair Specificity of Alkyl- and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles)

Terri A. Fairley, Richard R. Tidwell, Isaac Donkor, Noreen A. Naiman, Kwasi A. Ohemeng, Richard J. Lombardy, James A. Bentley, Michael Cory

Research output: Contribution to journalArticle

192 Citations (Scopus)

Abstract

A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA)·poly(dT), poly(dA-dT)-poly-(dA-dT), and poly(dG-dC)-poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (ΔTm) and viscosity. The compounds show a greater affinity for poly-(dA)-poly(dT) and poly(dA-dT)-poly(dA-dT) than for poly(dG-dC)-poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.

Original languageEnglish (US)
Pages (from-to)1746-1753
Number of pages8
JournalJournal of Medicinal Chemistry
Volume36
Issue number12
DOIs
StatePublished - Jan 1 1993
Externally publishedYes

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Base Pairing
Nucleic Acids
DNA
Hydrogen Bonding
Viscosity
polydeoxyadenylic acid-polythymidylic acid
Nitrogen
Hot Temperature
poly(dC-dG)
calf thymus DNA

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Drug Discovery

Cite this

Structure, DNA Minor Groove Binding, and Base Pair Specificity of Alkyl- and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles). / Fairley, Terri A.; Tidwell, Richard R.; Donkor, Isaac; Naiman, Noreen A.; Ohemeng, Kwasi A.; Lombardy, Richard J.; Bentley, James A.; Cory, Michael.

In: Journal of Medicinal Chemistry, Vol. 36, No. 12, 01.01.1993, p. 1746-1753.

Research output: Contribution to journalArticle

Fairley, Terri A. ; Tidwell, Richard R. ; Donkor, Isaac ; Naiman, Noreen A. ; Ohemeng, Kwasi A. ; Lombardy, Richard J. ; Bentley, James A. ; Cory, Michael. / Structure, DNA Minor Groove Binding, and Base Pair Specificity of Alkyl- and Aryl-Linked Bis(amidinobenzimidazoles) and Bis(amidinoindoles). In: Journal of Medicinal Chemistry. 1993 ; Vol. 36, No. 12. pp. 1746-1753.
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AU - Fairley, Terri A.

AU - Tidwell, Richard R.

AU - Donkor, Isaac

AU - Naiman, Noreen A.

AU - Ohemeng, Kwasi A.

AU - Lombardy, Richard J.

AU - Bentley, James A.

AU - Cory, Michael

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N2 - A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA)·poly(dT), poly(dA-dT)-poly-(dA-dT), and poly(dG-dC)-poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (ΔTm) and viscosity. The compounds show a greater affinity for poly-(dA)-poly(dT) and poly(dA-dT)-poly(dA-dT) than for poly(dG-dC)-poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.

AB - A series of bis(amidinobenzimidazoles) and bis(amidinoindoles) with varied linking chains connecting the aromatic groups and various modifications to the basic amidino groups have been prepared. The calf thymus (CT) DNA and nucleic acid homopolymer [poly(dA)·poly(dT), poly(dA-dT)-poly-(dA-dT), and poly(dG-dC)-poly(dG-dC)] binding properties of these compounds have been studied by thermal denaturation (ΔTm) and viscosity. The compounds show a greater affinity for poly-(dA)-poly(dT) and poly(dA-dT)-poly(dA-dT) than for poly(dG-dC)-poly(dG-dC). Viscometric titrations indicate that the compounds do not bind by intercalation. Molecular modeling studies and the biophysical data suggest that the molecules bind to the minor groove of CT DNA and homopolymers. Analysis of the shape of the molecules is consistent with this mode of nucleic acid binding. Compounds with an even number of methylenes connecting the benzimidazole rings have a higher affinity for DNA than those with an odd number of methylenes. Molecular modeling calculations that determine the radius of curvature of four defined groups in the molecule show that the shape of the molecule, as a function of chain length, affects the strength of nucleic acid binding. Electronic effects from cationic substituents as well as hydrogen bonding from the imidazole nitrogens also contribute to the nucleic acid affinity. The bis(amidinoindoles) show no structurally associated differential in nucleic acid base pair specificity or affinity.

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