Molecular Recognition of DNA by Rigid [n]-Polynorbornane-Derived Bifunctional Intercalators:  Synthesis and Evaluation of Their Binding Properties

Abstract

We have exploited the concept of multivalency in the context of DNA recognition, using novel chemistry to synthesize a new type of bis-intercalator with unusual sequence-selectivity. Bis-intercalation has been observed previously, but design principles for de novo construction of such molecules are not known. Our compounds feature two aromatic moieties projecting from a rigid, polynorbornane-based scaffold. The length and character of the backbone as well as the identity of the intercalators were varied, resulting in mono- or divalent recognition of the double helix with varying affinity. Our lead compound proved to be a moderately sequence-selective bis-intercalator with an unwinding angle of 27 degrees and a binding constant of about 8 microM. 9-aminoacridine rings were preferred over acridine carboxamides or naphthalimides, and a rigid [3]-polynorbornane scaffold was superior to a [5]-polynorbornane. The flexibility of the linker connecting the rings to the scaffold, although less influential, could affect the strength and character of the DNA binding.

Dinuclear organoiridium(III) mono- and bis-intercalators with rigid bridging ligands: Synthesis, cytotoxicity and DNA binding

“…An attractive design strategy to enhance both the affinity and specificity of DNA interactions is to combine an intercalator with other functionalities such as a second intercalator [12], a platinum-containing fragment capable of coordinative binding to nucleobases [13,14] or a DNA-alkylating agent [15]. Bis-intercalators might be expected to exhibit a greatly increased binding affinity for DNA which could also lead to improved cytotoxicity owing to both the increased number of DNA adducts formed and 0162-0134/$ -see front matter Ó 2009 Elsevier Inc. All rights reserved.…”

Factors Influencing Anion Binding Stoichiometry: The Subtle Influence of Electronic Effects

“…Furthermore, established cycloaddition methodologies [29] can also be exploited to create fused [n]polynorbornane frameworks for the purpose of encapsulating larger anionic, and possibly neutral, guests. [30,31] Herein the full synthesis of a family [10] of norbornenebased receptors 1-3 is presented, followed by the results of anion-binding studies using 1 H NMR and UV/Vis titration techniques.…”

Sequence‐Selective Organoiridium DNA Bis‐Intercalators with Flexible Dithiaalkane Linker Chains

“…[18] As a result of intercalation, the usual rotation of approximately 36°for neighbouring base-pairs is restricted to about 26°. [19,20] With few exceptions, it is generally accepted that the presence of an intercalator between two base-pairs will exclude the nearest neighbouring sites from being occupied by another intercalator. This nearest neighbour exclusion principle [21] stipulates that the intercalating moieties in an intrastrand bis-intercalator must sandwich a minimum of two base-pairs, which corresponds to a distance of about 10.2 Å (3 ϫ 3.4 Å intercalation sites).…”