Double threading through DNA: NMR structural study of a bis-naphthalene macrocycle bound to a thymine–thymine mismatch

Abstract

The macrocyclic bis-naphthalene macrocycle (2,7-BisNP), belonging to the cyclobisintercalator family of DNA ligands, recognizes T–T mismatch sites in duplex DNA with high affinity and selectivity, as evidenced by thermal denaturation experiments and NMR titrations. The binding of this macrocycle to an 11-mer DNA oligonucleotide containing a T–T mismatch was studied using NMR spectroscopy and NMR-restrained molecular modeling. The ligand forms a single type of complex with the DNA, in which one of the naphthalene rings of the ligand occupies the place of one of the mismatched thymines, which is flipped out of the duplex. The second naphthalene unit of the ligand intercalates at the A-T base pair flanking the mismatch site, leading to encapsulation of its thymine residue via double stacking. The polyammonium linking chains of the macrocycle are located in the minor and the major grooves of the oligonucleotide and participate in the stabilization of the complex by formation of hydrogen bonds with the encapsulated thymine base and the mismatched thymine remaining inside the helix. The study highlights the uniqueness of this cyclobisintercalation binding mode and its importance for recognition of DNA lesion sites by small molecules.

Differential Targeting of Unpaired Bases within Duplex DNA by the Natural Compound Clerocidin: A Valuable Tool to Dissect DNA Secondary Structure

“…For this reason is has been difficult to develop compounds that broadly target unusual DNA structures without affecting ds regions. Nakatani’s and Teulade-Fichou’s groups have recently reported compounds able to recognize sequence-specific mismatched DNA and hairpins [13], [33], [34], [35], [36], [37]. No structure-activity relationship can be drawn from these very diverse chemicals, which do not share structural similarities to CL.…”

Anthracene‐Based Cyclophanes with Selective Fluorescent Responses for TTP and GTP: Insights into Recognition and Sensing Mechanisms

“…In the 1990s, Lehn proposed the use of cyclophanes as artificial receptors for nucleosides and nucleotides . This work has inspired other groups to evaluate interactions between cyclophanes and nucleotides in aqueous solution . These macrocycles have also been found to interact with G‐quadruplex and show antiproliferative activity .…”

Design and Synthesis of Cyclic Mismatch‐Binding Ligands (CMBLs) with Variable Linkers by Ring‐Closing Metathesis and their Photophysical and DNA Repeat Binding Properties

“…Nowadays, cyclophanes have been an active area of research for their emerging perspective applicationsi ns upramolecular chemistry, [6][7][8][9] polymer chemistry, [10][11][12][13] molecular recognition, [14,18] antibacterial efficacy, [19] inhibitors of HIV proteinase, [20] molecular electronics and machines( or transistor and sensors), [21] as drug carri-ers, [22] and as catalystsi no rganic synthesis anda symmetric synthesis. [4,5,[26][27][28][29][30][31][32][33][34][35] Cyclophanes are traditionally employed to construct pstacked molecules. [4,5,[26][27][28][29][30][31][32][33][34][35] Cyclophanes are traditionally employed to construct pstacked molecules.…”

“…On the otherh and, heterophanes, [36,37] which are ac lass of cyclophanes containing heteroaromatic units are especially interesting for their immense biological activities. [27][28][29][30][31][32][33][34] The CMBL derivative belongs to an ew class of mismatch binders where the cyclophane skeleton conformationally fixes two aromatic heterocycles havingabase-recognition hydrogen-bonding surface. Polyazanaphthalenes represent as ignificant class of heterocyclicc ompounds for both synthetic and medicinal chemistry viewpoints.…”