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, 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.
Schwaller
M A
MA
Institut de Topologie et de Dynamique de Systèmes, CNRS URA 34, Université Paris 7, France.
Aubard
J
J
Dodin
G
G
D000470:Alkaloids / Q000493:pharmacokinetics*; D000818:Animals; D001665:Binding Sites / Q000187:drug effects / Q000502:physiology; D002021:Buffers; D002417:Cattle; D004247:DNA / Q000032:analysis / Q000187:drug effects* / Q000378:metabolism; D004347:Drug Interactions; D004611:Ellipticines / Q000032:analysis / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D012996:Solutions; D013696:Temperature; D013816:Thermodynamics; D013997:Time Factors
D000470:Alkaloids; D002021:Buffers; D004611:Ellipticines; D012996:Solutions; D004247:DNA