DNA polyintercalating drugs. Proton magnetic resonance studies of a new acridine dimer. Conformations and interactions with mono- and dinucleotides

Abstract

The conformation in aqueous solution of 1 acridine dimer which is able to bisintercalate in DNA (1,14-bis(2-methoxy-6-chloro-9-acridinyl)-1,5,10,14-tetraazatetradecane tetrahydrochloride) (AcDi) and its interactions with mono- and dinucleotides were investigated by fast Fourier transform PMR spectroscopy. Variations in chemical shifts of the most distinguishable protons of the acridine dimer with temperature bring evidence of a folded .dblarw. unfolded fast conformational equilibrium in the temperature range of 4-85.degree. C. Equilibrium parameters were estimated. The folded conformation was deduced from iso-shielding curves of the acridine ring. In the complex between AcDi and 3''- or 5''-AMP, the adenine ring is intercalated between the 2 acridine rings to give a sandwich-like complex. Studies of interaction with adenylyl(3'' .fwdarw. 5'')adenosine (Apa) show 2 different complexes in equilibrium with the 3'' or the 5'' moiety of ApA intercalated in the acridine dimer. These conclusions are derived from comparative studies with 2-methoxy-6-chloro-9-(3-dimethylaminopropylamino)acridine dihydrochloride which is the corresponding acridine monomer (AcMo). In that case the self-association constant was determined. A model of the AcMo-5''-AMP complex was deduced from the analysis of the chemical shifts of the adenine protons. In this model, the N10+-D bond of the acridine points toward the negatively charged phosphate of the nucleotide.