DNA binding and biological properties of bis and tris interacting molecules.

Abstract

Many biological processes are controlled by reversible bimolecular associations which are characterized by a high selectivity and a high binding constant. Such interactions are involved in the recognition of antigens by antibodies, of hormones by receptors and of nucleic acid sequences by proteins. Binding constants of the order of 108 to 1014 M–1 are often characteristic of such interactions. Many small organic molecules able to reversibly bind to nucleic acids have been discovered.1 Some of them are endowed with interesting biological properties. A few anti-tumor agents, such as actinomycin D doxorubicin, are DNA intercalating molecules.1 Many DNA binding molecules have also been found to be mutagenic. However, the binding constant for DNA of these molecules, which varies from 104 to 106 M–1, is much smaller than that of the natural DNA binding proteins2 which is generally larger than 1010 M–1. Therefore, we thought it might be of interest to design simple molecules capable of binding to DNA with an affinity constant higher than 1010 M–1. Such molecules might be able to compete in vivo with the DNA binding proteins which regulate genetic expression, and might be endowed with interesting biological properties. Animal cells might respond to agents able to form high affinity complexes with DNA in an unpredictable way. For instance, one can wonder whether the modifications of the DNA structure resulting from such complexes would be recognized by the cellular DNA repair machinery. Reversible DNA complexes of long life time might be difficult to distinguish from covalent DNA adducts. In this paper, we will describe the strategy which we used to design molecules able to bind to double stranded nucleic acids with high affinity. This strategy takes advantage of the characteristics of the DNA intercalation process and of the properties of oligomeric ligands. The properties of bis- and tris-intercalating molecules will be discussed. Because several antitumor agents were discovered among DNA bisintercalating molecules, the studies dealing with the mechanism of action of these compounds in relation to their DNA binding properties will also be reviewed.KeywordsBinding ConstantConformational DynamicDimeric SystemApparent Binding ConstantHigh Binding ConstantThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.