title: Selective Targeting of G-Quadruplex Structures by a Benzothiazole-Based Binding Motif.
abstract: A benzothiazole derivative was identified as potent ligand for DNA G-quadruplex structures. Fluorescence titrations revealed selective binding to quadruplexes of different topologies including parallel, antiparallel, and (3+1) hybrid structures. The parallel c-MYC sequence was found to constitute the preferred target with dissociation constants in the micromolar range. Binding of the benzothiazole-based ligand to c-MYC was structurally and thermodynamically characterized in detail by employing a comprehensive set of spectroscopic and calorimetric techniques. Job plot analyses and mass spectral data indicate noncooperative ligand binding to form complexes with 1:1 and 2:1 stoichiometries. Whereas stacking interactions are suggested by optical methods, NMR chemical shift perturbations also indicate significant rearrangements of both 5'- and 3'-flanking sequences upon ligand binding. Additional isothermal calorimetry studies yield a thermodynamic profile of the ligand-quadruplex association and reveal enthalpic contributions to be the major driving force for binding. Structural and thermodynamic information obtained in the present work provides the basis for the rational development of benzothiazole derivatives as promising quadruplex binding agents.
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt University Greifswald, Felix-Hausdorff-Strasse 4, 17487, Greifswald, Germany.
authors.forename: Ina
authors.initials: I
authors.lastname: Buchholz
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt University Greifswald, Felix-Hausdorff-Strasse 4, 17487, Greifswald, Germany.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Karg
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt University Greifswald, Felix-Hausdorff-Strasse 4, 17487, Greifswald, Germany.
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0002-3197-9472
authors.initials: J
authors.lastname: Dickerhoff
authors.affiliation: Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Adrian
authors.initials: A
authors.lastname: Sievers-Engler
authors.affiliation: Institute of Pharmaceutical Sciences, Eberhard Karls University Tübingen, Auf der Morgenstelle 8, 72076, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Lämmerhofer
authors.affiliation: Institute of Biochemistry, Ernst-Moritz-Arndt University Greifswald, Felix-Hausdorff-Strasse 4, 17487, Greifswald, Germany.
authors.forename: Klaus
authors.identifier: http://orcid.org/0000-0002-2736-6606
authors.initials: K
authors.lastname: Weisz
mesh_terms: D052160:Benzothiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D001665:Binding Sites; D002151:Calorimetry; D002942:Circular Dichroism; D054856:G-Quadruplexes; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D011485:Protein Binding; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry / Q000378:metabolism; D013816:Thermodynamics
chemical_list: D052160:Benzothiazoles; D008024:Ligands; D016271:Proto-Oncogene Proteins c-myc
keywords: G-quadruplexes; NMR spectroscopy; ligand effects; molecular recognition; noncovalent interactions