INTERACTION OF ACRIDINE DRUGS WITH DNA AND NUCLEOTIDES

Abstract

Abstract— At high phosphate‐to‐drug ratios acridine drugs intercalate between hydrogen bonded DNA base pairs causing significant changes in the physico‐chemical properties of DNA. The determination of the nature of the strong (or primary) interaction between acridine drugs and DNA is of great importance for elucidating the mode of the biological action of the drugs.Nanosecond measurements have revealed a fast depolarization of the fluorescence of proflavine, one of the most extensively studied acridines, bound to DNA. The electronic structure of the complex, however, is not substantially altered during the lifetime of the excited singlet electronic state of the drug. Guanine has been shown to be responsible for the quenching of the proflavine fluorescence upon binding to DNA. A temperature‐jump relaxation study has demonstrated a rather external complexation of this drug with the G‐C base pairs; this complex, whose formation occurs in the strong binding region, is distinct from the weak electrostatic complex.The findings that the binding ability of a series of acridines correlates with their basicity and that the drug–binding behavior of methylated DNA is significantly different from that of DNA suggested that specific forces may be also involved in the drug–DNA binding in addition to hydrophobic forces. Recent experiments employing molecular complexes of acridines with nucleotides as model systems have provided strong support for the specificity of the drug‐DNA interaction. Hydrogen bonding between the drug and reactive groups of the DNA bases that do not contribute directly to the stability of the helix may be involved in that interaction.The stoichiometry of the proflavine‐guanosine 5′‐phosphate complex is 1:1. Its association constant increases from 310 M‐1 when proflavine is in its ground electronic state, to 1550 M‐1, when proflavine is in its first excited singlet state. Thus, light absorbed by the drug alters its reactivity which, in turn, results in an appreciable increase in its ability to bind to the nucleotide. In view of the proposed importance of the drug–base interaction in explaining the mutagenic properties of acridine drugs and, in particular, of the proposed involvement of the G‐C base pairs, this finding emphasizes the possible importance of drug photoexcitation in acridine mutagenesis; it also contributes to the elucidation of photodynamic action.X‐ray diffraction studies have recently provided very interesting demonstrations of strong binding of 9‐aminoacridine and of the phenanthridine drug ethidium bromide to adenine‐uracil base pairs in the crystalline phase.The ability of photoexcited acridine drugs to inactivate viruses has been recently used for therapeutic purposes. The carcinogenic risk involved, however, is still under investigation.