Ligand‐Driven G‐Quadruplex Conformational Switching By Using an Unusual Mode of Interaction

Abstract

We report herein the successful design of the first molecule that induces the folding of the parallel human telomeric G-quadruplex from single-stranded DNA in the absence of added cation.[1] Ammonium ions stabilize quadruplex structures, [2] and K + ions have been shown to be separated by approximately 3.3 Å in the crystal structure of the human telomeric quadruplex.[3] Therefore, we synthesized 1 (Scheme 1) based on the hypothesis that the anthracene moiety would stack onto guanines, forming one of the external quartets and allowing the ammonium centers of 1, which are separated by approximately 3.4 Å, to induce the DNA folding through hydrogen bonding and cation-dipole interactions, mimicking K + ions within the central quadruplex channel. [4] Upon the addition of 1 to a solution containing the human telomeric DNA d[TTAGGG] 4 (telo24) at room temperature and free of added cation, we observed positive and negative CD signals at 263 and 240 nm, respectively, within 30 s (Figure 1). This resultant CD spectrum is characteristic of a parallel quadruplex.[5] The human telomeric quadruplex is highly polymorphic and can exist as parallel, [3] antiparallel,[6a] and mixed-type parallel/ antiparallel[6b] structures depending on strand orientation. However, ligand 1 appears to induce a single, parallel, quadruplex conformation. After addition of 10 equivalents of 1, an induced CD signal at the absorbance of achiral 1 (253 nm) was observed as a result of 1 sensing the DNA chirality in the complex. In control experiments, we observed that the addition of 20 equivalents (200 μM) of diethylene triamine (DETA) to a solution free of added cation, but containing telo24, did not induce quadruplex structures as seen by CD spectroscopy. Furthermore, ligand 2, in which an amide linkage reduces the protonation state and geometrical freedom of the molecule, also did not induce quadruplex formation under similar conditions (see the Supporting Information). These results suggest that the polyamine component of 1 is involved in a rather specific interaction with the DNA quadruplex.Quadruplex-specific stabilization by cations has an order of preference of K + >NH 4 + >Na + >Li + as a result of the relative free energies, hydration state, and ionic radius

Interaction of human telomeric DNA with N- methyl mesoporphyrin IX

“…The majority of these ligands induced transitions to antiparallel or mixed hybrid structures and only four to a parallel conformation. The list includes a conjugate of anthracene and polyamine (79), octacationic quaternary ammonium Zn(II) phtalocyanine (80), Ni(II) salphen complex with cyclic amine head groups (33) and ZnTMPyP4 (35). In all respects, NMM acts as a very potent driver of Tel22 structural rearrangement, equal or superior to the other four molecules reported in the literature.…”

In vivo veritas: Using yeast to probe the biological functions of G-quadruplexes

“…Many of these ligands interact with the outer quartet surfaces or intercalate between quartets of quadruplex stacks, making them perhaps relatively insensitive to particular loop structures of intra-molecular quadruplexes and thus relatively universal quadruplex ligands. Nonetheless, there is evidence that they can discriminate to some extent among different quadruplex folds [21,32,33]. Affinity chromatography using the selective quadruplex ligand N-methyl mesoporphyrin (NMM) coupled to acrylic beads has been used successfully to select quadruplexes from complex mixtures of nucleic acids [19,34], and so use of this ligand and probably others should be possible.…”

Selective RNA Versus DNA G‐Quadruplex Targeting by In Situ Click Chemistry

“…[13] Each solution was stirred at room temperature for six days, before trifluoroacetic acid (TFA) was added to denature the DNA (20 % aq). The mixture was monitored by LC-MS to simultaneously identify the nature and quantify the respective amounts of each product from a reaction that could, in principle, contain up to 24 cycloadducts, including 1,4-and 1,5-regioisomers (Figure 1 C).…”