Effects of ring substituents and linker chains on the bifunctional intercalation of diacridines into deoxyribonucleic acid

Abstract

Sedimentation experiments with closed circular duplex PM2 DNA and viscosity measurements with sonicated rodlike DNA fragments were performed to investigate unwinding and extension of the DNA helix associated with binding of homologous series of diacridines. When the acridine nuclei are linked via 9-amino substituents with chains permitting interchromophore separation in the critical region between 8.8 and 11.3 .ANG., it is found that substituents at positions 2, 3 and 6 restrict bifunctional intercalation to compounds capable of sandwiching at least 2 base pairs in the intercalated complex. Unsubstituted diacridines, and derivatives bearing an ethyl group at position 4, can bis-intercalate with a significantly shorter linking chain. The presence of amino groups in the linker does not affect the ability to bis-intercalate but increases the helix unwinding angle by 30-40% and decreases the helix extension per bound ligand molecule by 11-18%. Bifunctional reaction is observed with a diacridine linked via the 4-4'' positions, showing that 9-aminoacridine can intercalate in at least 2 major orientations with the 9 or 10 position directed toward the helix axis. Both orientations can be accommodated simultaneously within a single diacridine linked via the 9-4'' positions with a bridge sufficiently long to encompass 2 base pairs. An acridone substituted at positions 4 and 5 with positively charged side chains intercalates with a helix unwinding angle indistinguishable from that of ethidium, whereas an uncharged bis-acridone failed to yield a detectable complex with DNA. Tilorone dihydrochloride, a structurally similar antiviral drug, intercalated with an unwinding angle .apprx. 1/2 that of ethidium. The potentially bifunctional bisquinoline drug, dequalinium, causes relaxation of the supercoiling of PM2 DNA but probably not by simultaneous intercalation of both its chromophores.