A sequence-specific threading tetra-intercalator with an extremely slow dissociation rate constant

Abstract

A long-lived and sequence specific ligand-DNA complex would make possible the modulation of biological processes for extended periods. We have been investigating the threading polyintercalation approach to DNA recognition in which chains of aromatic units thread back and forth repeatedly through the double helix. Here we report the preliminary sequence specificity and detailed kinetic analysis of a structurally characterized threading tetraintercalator. Specific binding on a relatively long DNA strand was observed, strongly favoring a predicted 14-base pair sequence. Kinetic studies revealed a multi-step association process and specificity was found to derive primarily from large differences in dissociation rates. Importantly, the rate-limiting dissociation rate constant of the tetraintercalator complex dissociating from its preferred binding site was extremely slow, corresponding to a 16 day half-life, making it one of the longer non-covalent complex half-lives yet measured, and, to the best of our knowledge, the longest for a DNA binding molecule.

Exploiting the interactions of aromatic units for folding and assembly in aqueous environments

“…Not mentioned here is our extensive work with DNA-binding oligo-NDI molecules. 74-76 Considering the complex nature of aromatic interactions, the predictable stacking geometry of DAN and NDI in water provides a well-defined recognition motif to achieve higher order architectures. Because the stacking of electrostatically complementary aromatic units is driven in part by polar solvents, the construction of aromatic foldamers and more complex aromatic assemblies in water can be more rationally designed.…”

Single-molecule study of the CUG repeat–MBNL1 interaction and its inhibition by small molecules

“…By positioning the linking chain and triaminotriazine recognition units on opposite sides of the acridine unit, the bivalent complex likely requires a threading mechanism for binding (25). This design element was intentional with the goal of increasing the binding affinity through a higher residence time (26,27). …”

Thermodynamics and kinetic studies in the binding interaction of cyclic naphthalene diimide derivatives with double stranded DNAs

“…Higher DNA-binding constants, slower dissociation rates, and substantial sequence selectivity can be expected from the incorporation of two or more intercalating units into a polyfunctional ligand. 6,7 Researchers have already reported that naphthalene diimide derivatives act as DNA-targeting anticancer agents, and such derivatives have shown potent activity against cancer cell lines and telomerase. 13,14 Depending on the substituents, naphthalene diimide derivatives have shown selectivity toward AT-or GC-rich regions of DNA.…”

“…13,14 Depending on the substituents, naphthalene diimide derivatives have shown selectivity toward AT-or GC-rich regions of DNA. 4,6 We previously published our synthesis and evaluation of the binding of G-quadruplex and dsDNA with cNDI 1 and other cNDIs. 11,12 In the present study, the interaction of cNDI 1 and the newly designed cNDI 2 with dsDNA was analyzed by UV-Vis spectroscopy, CD spectroscopy, a topoisomerase I assay, and stoppedflow kinetics to characterize differences in binding mode and binding selectivity.…”

“…Recently, the same concept has been explored for bis-intercalating or cyclic intercalating derivatives of naphthalene diimide. [5][6][7][8][9][10] The interaction of a cyclic naphthalene diimide with DNA shows a unique catenated structure that dramatically stabilizes the complex. A new type of cyclic naphthalene http://dx.doi.org/10.1016/j.bmc.2015.05.046 0968-0896/Ó 2015 Elsevier Ltd. All rights reserved.…”