X-ray crystallographic study of DNA duplex cross-linking: simultaneous binding to two d(CGTACG)2 molecules by a bis(9-aminoacridine-4-carboxamide) derivative

Abstract

Acridine-4-carboxamides form a class of known DNA mono-intercalating agents that exhibit cytotoxic activity against tumour cell lines due to their ability to inhibit topoisomerases. Previous studies of bis-acridine derivatives have yielded equivocal results regarding the minimum length of linker necessary between the two acridine chromophores to allow bis-intercalation of duplex DNA. We report here the 1.7 Å resolution X-ray crystal structure of a six-carbon-linked bis(acridine-4-carboxamide) ligand bound to d(CGTACG)2 molecules by non-covalent duplex cross-linking. The asymmetric unit consists of one DNA duplex containing an intercalated acridine-4-carboxamide chromophore at each of the two CG steps. The other half of each ligand is bound to another DNA molecule in a symmetry-related manner, with the alkyl linker threading through the minor grooves. The two crystallographically independent ligand molecules adopt distinct side chain interactions, forming hydrogen bonds to either O6 or N7 on the major groove face of guanine, in contrast to the semi-disordered state of mono-intercalators bound to the same DNA molecule. The complex described here provides the first structural evidence for the non-covalent cross-linking of DNA by a small molecule ligand and suggests a possible explanation for the inconsistent behaviour of six-carbon linked bis-acridines in previous assays of DNA bis-intercalation.

Self‐Assembly of Functionalizable Two‐Component 3D DNA Arrays through the Induced Formation of DNA Three‐Way‐Junction Branch Points by Supramolecular Cylinders

“…[14] A bisacridine bisintercalator that binds four-way junctions [15] was shown to also bind other DNA topologies. [16] The use of cylinder-bound 3WJs should add stability and rigidity to the DNA frame and enable the introduction of cylinder-linked functionality into DNA-based materials. These functionalities may potentially be introduced through inherent properties of the metallocylinders, such as fluorescence, [17] or through groups grafted onto the cylinder structure.…”

Principles of Small Molecule-DNA Recognition

“…The two minor-groove pendant sugar groups were replaced by a p-xylene linker group through the exocyclic amino groups on each sugar ring, thus generating a single bis-intercalating molecule. It has been observed for bis-acridines (Hopcroft et al, 2006;see above), and also (Peek et al, 1994) in a molecule comprising two pyridocarbazole units, linked by a flexible aliphatic chain, which has been cocrystallized with the short duplex sequence d(CGCG). 5.31), has been shown to exhibit all of the enhanced DNA-binding properties predicted for a bis-intercalator.…”

“…5.18). 5.20) has been found, at least in the crystal lattice (Hopcroft et al, 2006) to form a novel noncovalent interhelix cross-linked arrangement 5.19).…”

Thread Insertion of a Bis(dipyridophenazine) Diruthenium Complex into the DNA Double Helix by the Extrusion of AT Base Pairs and Cross‐Linking of DNA Duplexes

“…Both acridine groups were shown to intercalate into neighboring DNA duplexes. [15] The main differences between the acridinebased molecules and the bis(dppz) Ru compound is that the DNA duplexes in the structure described herein are brought together in such a way that their major-groove sides confront one another, which is a feature not observed so far in crossinteractions. The two duplex DNA molecules that are bound by dppz moieties are held in place with a lower degree of freedom as compared to the bisacridine derivatives, thus restricting the interduplex angle to about 308.…”