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

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 (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.

Anti-Pneumocystis carinii pneumonia activity of dicationic 2,4-diarylpyrimidines

“…As expected, the monocation 15 does not effectively interact with DNA and it shows no activity against PCP in the immunosuppressed rat model. Compound 8 exhibits the strongest interaction with DNA in this series; analogous results have been noted for the tetrahydropyrimidine cationic center in other similar series of dicationic molcules [20,21]. There is no apparent direct relationship between topoisomerase II inhibition, modeled using the enzyme from Gardia lamblia, and DNA binding or in vivo anti-PCP activity.…”

“…Pentamidine and its analogs [19], dicationic bis-benzimidazoles [20,21], and more recently dicationic 2,5-diarylfurans [13] (the latter give calculated radius of curvature values of approximately 15 Å) have been shown to be effective in treating Pneumocystis carinii pneumonia (PCP) and topoisomerase II inhibition may be involved in their mode of action. Collectively, these observations led us to evaluate dicationic 2,4-diarylpyrimidines, which give radius of curvature values in the range predicted to be effective DNA binding agents [17] and which have been demonstrated to strongly bind to AT-rich DNA [14], for effectiveness against PCP.…”

Green and High Efficient Synthesis of 2-Aryl Benzimidazoles: Reaction of Arylidene Malononitrile and 1,2-Phenylenediamine Derivatives in Water or Solvent-Free Conditions

“…Several procedures have been reported for the synthesis of 2-substituted benzimidazoles: Condensation of 1,2-phenylenediamines with carboxylic acids, acid chlorides, nitriles, imidates and orthoesters under strong acidic conditions, sometimes combined with very high temperatures or useing microwave irradiation, [19]- [22] oxidative cyclodehydrogenation of 1,2-phenylenediamine and aldehydes in the presence of different oxidants [23]- [26], transition-metal-catalyzed intramolecular cyclization of 2-haloanilides and their analogues [27]- [29] and also the condensation reactions of 1,2-phenylenediamine with β-ketonitriles [30], β-ketoesters [31] [32], or β-diketones [33] under microwave radiation and high temperature conditions or in the presence of a catalyst. Although, all of these methods are widely employed, but they have drawbacks such as low yields, the use of expensive and toxic reagents, catalysts and solvents, long reaction times, formation of side-products, tedious work-up procedure, and in some cases, harsh reaction conditions are required.…”

Synthesis, DNA-Binding Activity and Cytotoxicity of Carbamate Derivatives of Hoechst 33258 in Breast Cancer MCF-7 Cells.

“…3) The spectroscopic characteristics of Hoechst 33258 family of ligands have brought them into wide use as DNA fluorophores, 5) but several have also shown potent activity against a number of microorganisms that lead to AIDS-related opportunistic infections, 6) as well as exhibiting cytotoxic activity. [7][8][9][10] In the course of our investigations of minor groove binding drugs, we reported a cytotoxicity and DNA-binding ability of carbamate derivatives of Hoechst 33258 with chloroalkyl and bromoalkyl moieties (Fig.…”