ABSTRACT
A set of AT-specific fluorescent dimeric bisbenzimidazoles DBPA(n) with linkers of different lengths bound to DNA in the minor groove were synthesized and their genetic, virological, and biochemical studies were performed. The DBPA(n) were shown to be effective inhibitors of the histon-like protein H-NS, a regulator of the DNA transcription factor, as well as of the Aliivibrio logei Quorum Sensing regulatory system in E. coli cells. Their antiviral activity was tested in model cell lines infected with herpes simplex virus type I. Also, it was found that DBPA(n) could inhibit catalytic activities of HIV-1 integrase at low micromolar concentrations. All of the dimeric bisbenzimidazoles DBPA(n) manifested fluorescent properties, were well soluble in water, nontoxic up to concentrations of 200 µM, and could penetrate into nuclei followed by binding to DNA.
Subject(s)
Bisbenzimidazole/chemistry , Bisbenzimidazole/pharmacology , DNA/chemistry , Aliivibrio/metabolism , Anti-Bacterial Agents/pharmacology , Bacterial Proteins/antagonists & inhibitors , Base Sequence , DNA/genetics , Drug Design , Escherichia coli/metabolism , Fluorescent Dyes , HIV Integrase , HIV Integrase Inhibitors/pharmacology , Ligands , Molecular Structure , Pyrroles , Quorum Sensing/physiology , Structure-Activity RelationshipABSTRACT
A series of new fluorescent symmetric dimeric bisbenzimidazoles DBP(n) bearing bisbenzimidazole fragments joined by oligomethylene linkers with a central 1,4-piperazine residue were synthesized. The complex formation of DBP(n) in the DNA minor groove was demonstrated. The DBP(n) at micromolar concentrations inhibit in vitro eukaryotic DNA topoisomerase I and prokaryotic DNA methyltransferase (MTase) M.SssI. The DBP(n) were soluble well in aqueous solutions and could penetrate cell and nuclear membranes and stain DNA in live cells. The DBP(n) displayed a moderate effect on the reactivation of gene expression.
Subject(s)
Bisbenzimidazole/analogs & derivatives , DNA/chemistry , DNA/drug effects , Fluorescent Dyes/chemical synthesis , Fluorescent Dyes/pharmacology , Animals , Antineoplastic Agents/chemical synthesis , Antineoplastic Agents/chemistry , Antineoplastic Agents/pharmacology , Bisbenzimidazole/chemical synthesis , Bisbenzimidazole/pharmacology , Cell Line , DNA/genetics , DNA-Cytosine Methylases/antagonists & inhibitors , Dimerization , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Fluorescent Dyes/chemistry , Gene Expression/drug effects , Humans , MCF-7 Cells , Mice , Microscopy, Fluorescence , Structure-Activity Relationship , Topoisomerase I Inhibitors/chemical synthesis , Topoisomerase I Inhibitors/chemistry , Topoisomerase I Inhibitors/pharmacologyABSTRACT
Microscopic size particles of the cholesteric double-stranded DNA (RNA) liquid-crystalline dispersions, containing the ions of the rare earth elements in their content, have been obtained for the first time. The properties of these particles differ from those of classical DNA cholesterics noticeably. The local concentration of the rare earth elements in a particle reaches 200 mg/ml. The particles of the liquid-crystalline dispersion of the (DNA-gadolinium) complex maintain the properties for a long time. The combination of the microscopic size of particles, high concentration of gadolinium in particles and their stability opens a way to practical application of this new biomaterial.
Subject(s)
DNA/chemistry , Gadolinium/chemistry , Liquid Crystals/chemistry , Neutron Capture Therapy , Circular Dichroism , Magnetics , Neutron Activation AnalysisABSTRACT
We describe the formation and properties of nanoconstruction that consists of the double-stranded DNA molecules located at distance of 35-50 A in the spatial structure of particles of their cholesteric liquid-crystalline dispersions and cross-linked by artificial nanobridges. The resulting nanostructures possess the peculiar spatial and optical properties.
