The preparation and characterisation of cyclam/anthraquinone macrocyle/intercalator complexes and their interactions with DNA

Abstract

A new series of macrocycle/intercalator adducts have been prepared from cyclam (1,4,8,11-tetraazacyclotetradecane) and the 1- and 2-substituted anthraquinones (1-[(2-aminoethyl)amino]anthracene-9,10-dione (1C2mac), 1-[(3-aminopropyl)amino]anthracene-9,10-dione (1C3mac), 2-[(3-aminopropyl)amino]anthracene-9,10-dione (2C3mac)). The copper complexes of two of these adducts were prepared and the crystal structure of the complex of 1C2mac ([Cu(1C2mac)(CH₃CN)₂](PF₆)₂.0.2H₂O) was determined as the hexafluorophosphate salt. The equilibrium constants for the binding to DNA of 1C2-mac, with and without the copper added, were found by UV titrations to be 4.7 × 10³ M⁻¹ and 6.2 × 10³ M⁻¹, respectively. Reaction with plasmid DNA allowed comparison between the effects of the cyclam/anthraquinone adducts, their copper complexes and the intercalators alone. Addition of the macrocycle increased the extent and effect of DNA intercalation and addition of copper increased the effect still further. The adducts with the longer side chains caused substantially more unwinding of the DNA. None of the adducts inhibited cleavage at dGpG or dGpC sites by restriction enzymes. Molecular modelling was used to investigate the effects of the side chain for a number of possible DNA binding modes. These models reveal that intercalation is not significantly interfered with by the presence of the macrocycle, irrespective of the position of attachment. The increased unwinding caused by adducts with the longer side chain is therefore most likely to be due to specific interactions between the macrocycle and the DNA.