Topologically Constrained Bifunctional Intercalators: DNA Intercalation by a Macrocyclic Bisacridine

Abstract

A topologically novel DNA bifunctional intercalator, 4, has been synthesized and its DNA binding compared with the binding of the monointercalator 9-aminoacridine (6) and spermine bisacridine (5), a known bisintercalator. Water-soluble macrocyclic bisacridine 4 was synthesized by reaction of 4-(bromomethyl)-9-chloroacridine with N,N'-bis(2-mercaptoethyl)succinamide and base. The resulting dichloride was converted to the corresponding bis(9-phenoxyacridine), which reacted with spermine tetrahydrochloride to form macrocyclic bisacridine 4. At a 1:10 ratio of 4 to calf thymus DNA phosphate, a ΔTm of >40 °C was measured, which indicates a high binding affinity. Viscometric analysis of helix extension using sonicated calf thymus DNA gave slopes for compounds 4 and 5 that were much greater than that for 6. Metachromic shifts were observed in the absorption spectra of 4 upon addition of DNA. These metachromic shifts were similar to those shown by 5 and 6 under the same conditions. Additions of 4 to closed circular supercoiled plasmid DNA (pOP1 Δ6) removed and reversed the supercoiling as measured by the changes in the viscometric properties of the plasmid. The similarities in binding data obtained for macrocycle 4 and the known bisintercalator spermine bisacridine (5) indicate that the former also binds to DNA as a bifunctional intercalator. © 1989, American Chemical Society. All rights reserved.