DNA-Binding of Drugs Used in Medicinal Therapies

Abstract

The interactions of various low-molecular weight substances with DNA are naturally relevant mechanisms in the cellular cycle and so also used in medicinal treatment. Depending on the particular drug structure, DNA-binding modes like groove-binding, intercalating and/or stacking, give rise to supramolecular assemblies of the polynucleotides, as well as influence the DNA-protein binding. In this review, we compare the underlying molecular structures, including general aspects of DNA sequences, with the benefit in medicinal treatment. While so far interest in this field had mainly been devoted to isolated nucleic acid/drug interactions, the present paper will focus on drug efficiencies generating and influencing supramolecular organizations and their complex sequence-dependent structure-activity codes. In particular, the attention will be directed to stereoelectronic relationships. Spatial enantioselective properties are discussed in details. As examples, the drug self-assemblies, as well as the influence of drugs on supramolecular DNA formations are described. A hypothetical connection between drug-influenced DNA-toroids and the formation of micronuclei in tissues will be interpreted.

Comparison of the binding stoichiometries of positively charged DNA-binding drugs using positive and negative ion electrospray ionization mass spectrometry

“…In contrast, negative ion spectra showed ions for free dsDNA and complexes containing 1-5 bound EtBr molecules (data not shown). This compound is known to intercalate into DNA and is used extensively in molecular biology laboratories for DNA staining [1]. Thus while we have speculated that the second Hc molecule observed to bind in the positive ion spectra may result from partial intercalation, the comparison with a classical intercalator such as ethidium bromide supports the notion that the nature of the binding of the second Hc may be in fact more complex.…”

“…The data presented suggest that comparison of positive and negative ion ESI-MS spectra might provide an insight into various binding modes in both solution and the gas phase. [1]. It has been estimated that in order to specifically target a unique regulatory sequence within a gene in the human genome, eleven DNA base pairs have to be recognized by a drug [2].…”

“…Consequently, efforts have been directed towards the synthesis of novel compounds, often based on natural products that interact non-covalently with extended DNA sequences that have particular characteristics (e.g., ATrich promoters of genes). Drugs that bind non-covalently, but with relatively high affinity to DNA include minor groove-binders and intercalators [1].…”

“…Examples of this class of drug are Hoechst 33258 and distamycin (Hc and Dm, respectively; Figure 1a and b). Intercalators are planar aromatic polycyclic compounds that slide between stacked base pairs of the DNA double helix [1]. Substitution on the aromatic rings can confer enhanced specificity to the drug-DNA interaction.…”

The role of encapsulation by β-cyclodextrin in the interaction of raloxifene with macromolecular targets: a study by spectroscopy and molecular modeling

“…Similarly, drug molecules binding with macromolecular biological targets including blood proteins and DNA have been explored for several years [23][24][25][26]. However, even though cyclodextrins are known carriers that help in the sustained release of drugs, reports on the role of such carrier molecules in bringing the encapsulated molecules towards protein or DNA and their role in modulating the binding of drugs to the targets are scarce.…”