title: Determination of binding modes and binding constants for the complexes of 6H-pyrido[4,3-b]carbazole derivatives with DNA.
abstract: The binding modes and binding constants for the complexes of forty types of pyridocarbazole derivatives 1-40 with double stranded DNAs (dsDNAs) were reported. The binding modes were determined by a combination of a deflection spectroscopy and orientation of the corresponding molecule in the DNA-based film with chain alignment. All of the compounds exhibited the intercalation-binding mode. Its binding constants Kafor the complexes, determined by quartz crystal microbalance (QCM), varied from 1.7×105to 4.5×107M-1according to the substituents on the pyridocarbazole framework and the sequences of dsDNA. The binding constants Kaof pyridocarbazole derivatives possessing the 2-(ω-amino)alkyl group and 5-(ω-amino)alkylcarbamyl group were larger than those of the corresponding ω-ureido derivatives. These ω-amino compounds exhibited strong GC base-pair preference in complexation. The Kavalues decreased with the increasing NaCl concentration. It was clarified by a molecular modeling that the framework of the 2-tethered ω-amino derivative was completely overlapped with the stacking GC base-pairs leading to the formation of the stable intercalative-complex, and that the framework of the 5-tethered ureido derivative was half overlapped leading to the formation of the unstable complex. Furthermore, there were good linear relationships between lnKaand the relative stabilities Srelof the complexes. Contrary to our expectation, there was no linear relationship between lnKaand IC50against Sarcoma-180, NIH3T3, and HeLa S-3 cell lines.
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan.
authors.forename: Akihito
authors.initials: A
authors.lastname: Shimazu
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan.
authors.forename: Masashi
authors.initials: M
authors.lastname: Kawagoshi
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan.
authors.forename: Haruaki
authors.initials: H
authors.lastname: Kurasaki
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan.
authors.forename: Asako
authors.initials: A
authors.lastname: Kato
authors.affiliation: Nanomaterials Laboratory, National Institute for Materials Science (NIMS), Tsukuba, Ibaraki 305-0003, Japan.
authors.forename: Nahoko
authors.initials: N
authors.lastname: Morii
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Sakai
authors.affiliation: Department of Pure and Applied Chemistry, Faculty of Science and Technology, Tokyo University of Science (RIKADAI), Noda, Chiba 278-8510, Japan. Electronic address: konaka@rs.noda.tus.ac.jp.
authors.forename: Takeo
authors.initials: T
authors.lastname: Konakahara
mesh_terms: D000818:Animals; D001665:Binding Sites / Q000187:drug effects; D002227:Carbazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002470:Cell Survival / Q000187:drug effects; D004247:DNA / Q000737:chemistry / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D041681:NIH 3T3 Cells; D058525:Quartz Crystal Microbalance Techniques; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
chemical_list: D002227:Carbazoles; C041514:carbazole; D004247:DNA
keywords: 6H-Pyrido[4,3-b]carbazole; Binding constant; Cytotoxic activity; DNA; Deflection spectroscopy; Ellipticine; GC base-pair preference; Intercalation; Molecular modeling; QCM; Salt effects; pH dependence