Antitumour 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 acridine derivatives (1-5) and salmon testes DNA have been studied using several physicochemical techniques. These include spectrophotometric analysis, fluorescence quenching, thermal denaturation, and circular and linear dichroism. In order to compare the extent of the DNA binding by compounds 1-5 in their neutral and cationic forms, all experiments have been conducted at pH 7.4 and at pH 5.0. Other polynucleotides, including [Poly(dA-dT)]2 and [Poly(dG-dC)]2, were used in order to study the DNA base-pair binding specificity of these novel annelated acridine derivatives. The results indicate that the new polycyclic acridines display the following properties: (i) they are strong DNA-binding ligands with affinities 10- to 400-fold greater than that of acridine, 3- to 100-fold greater than that of m-AMSA (6) and 1- to 23-fold greater than that of proflavine at physiological pH (7.4); (ii) they have stronger DNA-binding activity at pH 5.0 as a result of the N-protonation of 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 form a molecular complex with DNA undergoing intercalation inside the duplex macromolecule, as shown by linear and circular dichroism. Nevertheless, circular dichroism studies reveal alternative binding modes at low DNA: drug ratios.
Giménez-Arnau
E
E
Department of Pharmaceutical Sciences, University of Nottingham, UK.
Missailidis
S
S
Stevens
M F
MF
D000166:Acridines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry* / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D002942:Circular Dichroism; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004355:Drug Stability; D006358:Hot Temperature; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008297:Male; D011084:Polycyclic Aromatic Hydrocarbons / Q000737:chemistry* / Q000494:pharmacology*; D012474:Salmon; D013050:Spectrometry, Fluorescence; D013056:Spectrophotometry, Ultraviolet
D000166:Acridines; D000970:Antineoplastic Agents; D011084:Polycyclic Aromatic Hydrocarbons; D004247:DNA