ANTITUMOR POLYCYCLIC ACRIDINES - PART-2 - PHYSICOCHEMICAL STUDIES ON THE INTERACTIONS BETWEEN DNA AND NOVEL POLYCYCLIC ACRIDINE-DERIVATIVES

The noncovalent interactions between a series of new polycyclic acridi ne derivatives (1-5) and salmon testes DNA have been studied using sev eral physicochemical techniques. These include spectrophotometric anal ysis, fluorescence quenching, thermal denaturation, and circular and l inear dichroism. In order to compare the extent of the DNA binding by compounds 1-5 in their neutral and cationic forms, all experiments hav e been conducted at pH 7.4 and at pH 5.0. Other polynucleotides, inclu ding [Poly(dA-dT)](2) and [Poly(dG-dC)](2), were used in order to stud y the DNA base-pair binding specificity of these novel annelated acrid ine derivatives The results indicate that the new polycyclic acridines display the following properties: (i) they are strong DNA-binding lig ands with affinities 10- to 400-fold greater than that of acridine, 3- to 100-fold greater than that of m-AMSA (6) and I-to 23-fold greater than that of proflavine at physiological pH (7.4); (ii) they have stro nger DNA-binding activity at pH 5.0 as a result of the N-protonation o f the aromatic chromophore; (iii) they bind more selectively to [Poly( dA-dT)](2) polynucleotide than to [Poly(dG-dC)](2) polynucleotide; (iv ) within the series compound 3 binds to DNA less than compounds 1, 2, 4 and 5 at both pH values studied; and (v) the polycyclic acridines fo rm a molecular complex with DNA undergoing intercalation inside the du plex macromolecule, as shown by linear and circular dichroism. Neverth eless, circular dichroism studies reveal alternative binding modes at low DNA:drug ratios.