Specific molecular interactions of acridine drugs in complexes with topoisomerase II and DNA. SERS and resonance Raman study of m‐AMSA in comparison with o‐AMSA

Abstract

AbstractMolecular interactions of a potent DNA‐topoisomerase II (Topo II) inhibitor, m‐AMSA [4′‐(9‐acridinylamino)methanesulphon‐m‐anisidide] and of its less active isomer o‐AMSA in complexes with plasmid DNA, Topo II and Topo II‐mediated ternary cleavable complexes were studied by means of surface‐enhanced Raman scattering (SERS) spectroscopy. Models for the participation of these drugs in the complexes were proposed according to the analysis of the main vibrational modes of the acridine chromophores in the SERS and resonance Raman (RR) spectra of m‐AMSA in comparison with the structurally close derivatives o‐AMSA and 9‐aminoacridine (9AA). It was found that, under the conditions used, the adsorption on the silver colloid does not perturb the Raman spectra of acridine chromophores. The SERS data indicate the intercalation of the planar acridine moiety within DNA for 9AA and for both o‐AMSA and m‐AMSA, without pronounced differences for the meta and ortho isomers. The DNA intercalation is likely to involve a μ‐μ interaction between the acridine and DNA base pairs, but without contacts via the nitrogen of the acridine ring. This is because the spectral changes observed in the drug‐DNA complexes of m‐and o‐AMSA are different from those observed on acridine deprotonation. In fact, it is the NH group of the side‐chain of the drug that we propose to interact with the negatively charged phosphates or edges of DNA and stabilizes the arrangement of the external anilino ring in the minor groove of DNA. The DNA intercalation seems to be present for the acridine moiety of both isomers in the ternary cleavable complexes. However, in the latter the side‐chain of m‐AMSA, but not of o‐AMSA, has been found additionally to participate in specific (enzymatic activity‐dependent) interactions with Topo II. The SERS data indicate the ability of m‐AMSA to interact specifically with the enzyme alone. The specific m‐AMSA‐Topo II interactions on formation of the cleavable ternary complex and/or directly with the enzyme should play a key role in the Topo II inhibition and therefore in the anti‐tumour activity of the drug.