title: The interaction of ellipticine derivatives with nucleic acids studied by optical and 1H-nmr spectroscopy: effect of size of the heterocyclic ring system.
abstract: The DNA interaction of derivatives of ellipticine with heterocyclic ring systems with three, four, or five rings and a dimethylaminoethyl side chain was studied. Optical spectroscopy of drug complexes with calf thymus DNA, poly[(dA-dT).(dA-dT)], or poly[(dG-dC).(dG-dC)] showed a 10 nm bathochromic shift of the light absorption bands of the pentacyclic and tetracyclic compounds upon binding to the nucleic acids, which indicates binding by intercalation. For the tricyclic compound a smaller shift of 1-3 nm was observed upon binding to the nucleic acids. Flow linear dichroism studies show that the geometry of all complexes is consistent with intercalation of the ring system, except for the DNA and poly[(dG-dC).(dG-dC)] complexes of the tricyclic compound, where the average angle between the drug molecular plane and the DNA helix axis was found to be 65 degrees. One-dimensional 1H-nmr spectroscopy was used to study complexes between d(CGCGATCGCG)2 and the tricyclic and pentacyclic compounds. The results on the pentacyclic compound show nonselective broadening due to intermediate chemical exchange of most oligonucleotide resonances upon drug binding. The imino proton resonances are in slow chemical exchange, and new resonances with upfield shifts approaching 1 ppm appear upon drug binding, which supports intercalative binding of the pentacyclic compound. The results on the tricyclic compound show more rapid binding kinetics and very selective broadening of resonances. The data suggest that the tricyclic compound is in an equilibrium between intercalation and minor groove binding, with a preference to bind close to the AT base pairs with the side chain residing in the minor groove.
authors.affiliation: Department of Medical Biochemistry and Biophysics, University of Umeå, Sweden.
authors.forename: G
authors.initials: G
authors.lastname: Behravan
authors.forename: M
authors.initials: M
authors.lastname: Leijon
authors.forename: U
authors.initials: U
authors.lastname: Sehlstedt
authors.forename: B
authors.initials: B
authors.lastname: Nordén
authors.forename: H
authors.initials: H
authors.lastname: Vallberg
authors.forename: J
authors.initials: J
authors.lastname: Bergman
authors.forename: A
authors.initials: A
authors.lastname: Gräslund
mesh_terms: D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D002417:Cattle; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004611:Ellipticines / Q000737:chemistry / Q000378:metabolism*; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism; D013053:Spectrophotometry
chemical_list: D004611:Ellipticines; D009838:Oligodeoxyribonucleotides; D004247:DNA