Kinetic and thermodynamic studies on drug-DNA interactions in the ellipticine series

The temperature-jump (T-jump) method has been used to investigate the binding mechanism to calf-thymus DNA of ellipticine and some of its derivatives. The results show that the plant alkaloid, ellipticine, interacts with DNA at a unique intercalation site whereas most of its synthetic derivatives, s...

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Bibliographic Details
Published inAnti-cancer drug design Vol. 5; no. 1; p. 77
Main Authors Schwaller, M A, Aubard, J, Dodin, G
Format Journal Article
LanguageEnglish
Published United States 01.02.1990
Subjects
Alkaloids - pharmacokinetics
Animals
Binding Sites - drug effects
Binding Sites - physiology
Buffers
Cattle
DNA - analysis
DNA - drug effects
DNA - metabolism
Drug Interactions
Ellipticines - analysis
Ellipticines - pharmacokinetics
In Vitro Techniques
Solutions
Temperature
Thermodynamics
Time Factors
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Summary:The temperature-jump (T-jump) method has been used to investigate the binding mechanism to calf-thymus DNA of ellipticine and some of its derivatives. The results show that the plant alkaloid, ellipticine, interacts with DNA at a unique intercalation site whereas most of its synthetic derivatives, such as ellipticinium, 9-hydroxy-ellipticinium and related alkyl-oxazolopyridocarbazoles recognize two distinct DNA sites. Parallel analysis of kinetic data and DNA lengthening abilities of these derivatives suggests that only one of these two DNA sites is an intercalation site. Owing to the determination of the genuine number of drug-DNA complexes (inferred from T-jump experiments) and with the results of thermodynamic investigations (Van't Hoff plots), further characterization of the molecular interactions involved in the binding process was proposed. Thus, the formation of the unique intercalation complex of ellipticine was found to be entropy driven whereas binding of drugs which recognize the second class of binding sites was essentially enthalpy driven. These different thermodynamic behaviors suggest that intercalation essentially results from hydrophobic solvent structure effects in contrast to the second binding mode which principally arises from hydrogen bonding interactions through DNA grooves.
ISSN:0266-9536