title: Spectroscopic and calorimetric studies on the DNA recognition of pyrrolo[2,1-c][1,4]benzodiazepine hybrids.
abstract: DNA binding of two hybrid ligands composed of an alkylating pyrrolo[2,1-c][1,4]benzodiazepine (PBD) moiety tethered to either a naphthalimide or a phenyl benzimidazole chromophore was studied by DNA melting experiments, UV and fluorescence titrations, CD spectroscopy and isothermal titration calorimetry (ITC). Binding of both hybrids results in a remarkable thermal stabilization with an increase of DNA melting temperatures by up to 40 degrees C for duplexes that allow for a covalent attachment of the PBD moiety to guanine bases in their minor groove. CD spectroscopic measurements suggest that the naphthalimide moiety of the drug interacts through intercalation. In contrast, the PBD-benzimidazole hybrid binds in the DNA minor groove with a preference for (A,T)(4)G sequences. Whereas the binding of both ligands is enthalpy-driven and associated with a negative entropy, the benzimidazole hybrid exhibits a less favourable binding enthalpy that is counterbalanced by a more favourable entropic term when compared to the naphthalimide hybrid.
authors.affiliation: Institut für Biochemie, Ernst-Moritz-Arndt-Universität Greifswald, Felix-Hausdorff-Str. 4, D-17487 Greifswald, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Rettig
authors.forename: Ahmed
authors.initials: A
authors.lastname: Kamal
authors.forename: R
authors.initials: R
authors.lastname: Ramu
authors.forename: Judith
authors.initials: J
authors.lastname: Mikolajczak
authors.forename: Klaus
authors.initials: K
authors.lastname: Weisz
mesh_terms: D001483:Base Sequence; D001569:Benzodiazepines / Q000737:chemistry*; D001665:Binding Sites; D002151:Calorimetry; D004247:DNA / Q000737:chemistry*; D009691:Nucleic Acid Denaturation; D013057:Spectrum Analysis; D013816:Thermodynamics; D044366:Transition Temperature
chemical_list: D001569:Benzodiazepines; D004247:DNA