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

Molecular interactions of a potent DNA-topoisomerase II (Topo II) inhi bitor, nt-AMSA [4'-(9-acridinylamino)methanesulphon-m-anisidide] and o f its less active isomer o-AMSA in complexes with plasmid DNA, Topo II and Topo II-mediated ternary cleavable complexes were studied by mean s of surface-enhanced Raman scattering (SERS) spectroscopy. Models for the participation of these drugs in the complexes were proposed accor ding to the analysis of the main vibrational modes of the acridine chr omophores in the SERS and resonance Raman (RR) spectra of m-AMSA in co mparison with the structurally close derivatives o-AMSA and 9-aminoacr idine (9AA). It was found that, under the conditions used, the adsorpt ion on the silver colloid does not perturb the Raman spectra of acridi ne chromophores. The SERS data indicate the intercalation of the plana r acridine moiety within DNA for 9AA and for both o-AMSA and nl-AMSA, without pronounced differences for the meta and ortho isomers. The DNA intercalation is likely to involve a pi-pi interaction between the ac ridine and DNA base pairs, but without contacts via the nitrogen of th e acridine ring. This is because the spectral changes observed in tbe 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-cha in of the drug that we propose to interact with the negatively charged phosphates or edges of DNA and stabilizes the arrangement of the exte rnal anilino ring in tbe minor groove of DNA, The DNA intercalation se ems to be present for the acridine moiety of both isomers in the terna ry cleavable complexes. However, in the latter the side-chain of m-AMS A, but not of o-AMSA, has been found additionally to participate in sp ecific (enzymatic activity-dependent) interactions with Topo II. The S ERS data indicate the ability of m-AMSA to interact specifically with the enzyme alone. The specific m-AMSA-Topo II interactions on formatio n of the cleavable ternary complex and/or directly with the enzyme sho uld play a key role in the Topo II inhibition and therefore in the ant i-tumour activity of the drug.