Structure, DNA minor groove binding, and base pair specificity of alkyl- and aryl-linked bis(amidinobenzimidazoles) and bis(amidinoindoles)

• Published in: Journal of medicinal chemistry 1993-06, Vol.36 (12), p.1746-1753
• Main Authors: Fairley, Terri A, Tidwell, Richard R, Donkor, Isaac, Naiman, Noreen A, Ohemeng, Kwasi A, Lombardy, Richard J, Bentley, James A, Cory, Michael
• Format: Article
• Language: English
• Subjects: Amidines - chemical synthesis; Amidines - metabolism; Animals; Antineoplastic agents; Base Composition; Benzimidazoles - chemical synthesis; Benzimidazoles - chemistry; Benzimidazoles - metabolism; Binding Sites; Biological and medical sciences; Cattle; Chemical Phenomena; Chemistry, Physical; Chemotherapy; DNA - metabolism; Electrochemistry; Hot Temperature; Hydrogen Bonding; Indoles - chemical synthesis; Indoles - metabolism; Medical sciences; Molecular Structure; Pharmacology. Drug treatments; Poly dA-dT - metabolism; Polydeoxyribonucleotides - metabolism; Structure-Activity Relationship; Viscosity
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm00064a008

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 (delta Tm) 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.