Mono‐, bis‐ and tetra‐acridine ligands: Synthesis, X‐ray structural determination and dynamic fluorescence microscopic studies on the modification of the higher order structure of DNA

Abstract

AbstractA series of mono‐, bis‐ and tetra‐acridine ligands were prepared and their effects on the higher order structure of DNA were studied by dynamic fluorescence microscopy. The single‐crystal structure of the bis‐acridine derivative N‐[2‐(dimethylamino) ethyl]‐4‐[2‐(9‐acridinylamino)benzamido]‐2‐(9‐acridinylamino)benzamide trihydrochloride (4) was determined, and shows that the molecule is sufficiently flexible to fold into an intramolecular stacking interaction in the crystal, supporting earlier hydrodynamic evidence that this compound can bis‐intercalate into DNA forming a single base pair (bp) sandwich complex. The corresponding tetra‐acridine analogue 1,11‐bis[4‐[2‐(9‐acridinylamino)benzamido]‐2‐(9‐acridinylamino)phenyl]‐1,11‐dioxo‐6‐methyl‐2,6,10‐triazaundecane pentahydrochloride (6) was synthesized, and dynamic fluorescence microscopy was used to study the effects of 4 and 6 on the higher order structure of large T4 DNA molecules (166 kbp), by measuring the average long‐axis legth (persistence length, l) of the complexes. The mono‐intercalating ligand acridine orange (5) increase l, whereas the bisintercalating diacridine 4 has no apparent effect and the putative multi‐intercalating tetracridine derivative 6 decreases l by compacting the higher order DNA structure. These results demonstrate the usefulness of the technique for directly observing ligand–DNA complexes, and show that ligands with suitably positioned multiple binding sites can influence the higher order structure of DNA (and thus possibly gene expression).