Thermodynamics of drug-DNA interactions: entropy-driven intercalation and enthalpy-driven outside binding in the...

Viscosimetric and kinetic results allow one to characterize three modes of DNA binding in the ellipticine series: (1) Ellipticine and its 9 methoxy derivative, which present maximal DNA lengthening properties and bind DNA through a single step mechanism, can be considered as pure intercalators. (2) Ellipticinium derivatives and short-chain substituted oxazolopyridocarbazoles, which present intermediate DNA lengthening properties, bind DNA through a two-step mechanism, one being intercalation. (3) Long-chain substituted oxazolopyridocarbazole derivatives, which display the smallest DNA lengthening properties, bind DNA through a single-step mechanism, probably resulting from an outside binding mode. The viscosimetric and kinetic results are compared with the thermodynamic results obtained from the temperature dependence of the binding constants. It appears that drugs binding on the outside of the DNA double helix tend to have large enthalpy and small entropy contributions, whereas pure intercalating drugs have contributions from both enthalpy and entropy, with entropy dominating by about 2:1. Drugs showing two binding modes exhibit a continuum between the aforementioned extremes, with no breaks in behavior. From this comparison, a correlation between thermodynamic data and DNA binding modes is proposed. Possible molecular implications of both enthalpy and entropy to DNA binding free energy are discussed.