ANTITUMOR POLYCYCLIC ACRIDINES - PART 4 - PHYSICOCHEMICAL STUDIES ON THE INTERACTIONS BETWEEN DNA AND NOVEL TETRACYCLIC ACRIDINE-DERIVATIVES

The non-covalent interactions between a series of new tetracyclic acri dine derivatives (5-11) and DNA have been studied by spectrophotometri c analysis, fluorescence quenching, thermal denaturation, and circular and linear dichroism. In order to compare the extent of the DNA bindi ng by compounds 5-11 in their neutral and cationic forms, all experime nts were conducted at pH 7.4 (physiological pH) and 5.0. The results i ndicated that compounds 5-11 are strong DNA-binding ligands with DNA a ffinities comparable to that of m-AMSA (1) or even higher. They showed a stronger DNA binding activity at pH 5.0 as a result of the N-proton ation of the pyridoacridine aromatic chromophore. Ethidium-DNA fluores cence assays showed an A-T base pair preference of the binding disting uishing these novel compounds from simple acridines which show a sligh t G-C base pair preference. Circular and linear dichroism studies indi cated that the drugs bind to DNA by undergoing intercalation inside th e duplex macromolecule at high DNA:drug ratios and revealed alternativ e binding modes at low DNA:drug ratios.