Résumé
One class of small molecules with therapeutic potential for treatment of cancer functions as transcription inhibitors via interaction with double-stranded DNA. Majority of the studies of the interaction with DNA have so far been reported under conditions nonexistent in vivo. Inside the cell, DNA is present in the nucleus as a complex with proteins known as chromatin. For the last few years we have been studying the interaction of these DNA-binding small molecules at the chromatin level with emphasis on the drug-induced structural alterations in chromatin. Our studies have shown that at the chromatin level these molecules could be classified in two broad categories: single-binding and dual-binding molecules. Single-binding molecules access only DNA in the chromatin, while the dual-binding molecules could bind to both DNA and the associated histone(s). Structural effects of the DNA-binding molecules upon chromatin in light of the above broad categories and the associated biological implications of the two types of binding are discussed.
Résumé
DNA binding compounds were previously shown to bind to the right-handed DNA forms and hybrid B-Z forms in a highly cooperative manner and indicate that structural specificity plays a key role in a ligand binding to DNA. In this study, the modes of binding and structural specificity of agents to unusual DNA are examined by a variety of fluorescence techniques (intensity, polarization and quenching, etc.) to explore a reliable method to detect the association environment of ligands to deoxyoligonucleotides initially containing a B-Z junction between the left-handed Z-DNA and right-handed B-DNA. The results of fluorescence energy transfer measurement demonstrated that the ligand molecules bind to the allosterically converted DNA structures by intercalation. In the absence of high-resolution structural data, this fluorescence energy transfer measurement allowed reliable measures and infer the binding environment of ligands to the allosteric DNA structures.