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.

Plant‐Derived Stilbenoids as DNA‐Binding Agents: From Monomers to Dimers

“…For the here studied systems featured by 1 : 2 or 1 : 3 DNA/ligand binding stoichiometries, the obtained binding constants were considered only as apparent constants. Indeed, in the case of multiple binding events which, appearing unresolved when following spectroscopic changes, can be represented only by a simplified model based on independent and equivalent sites, as is our case, only averaged constant values over all the occurring binding events can be extrapolated [49,50] . Hence, the here obtained data allow only a rough estimation of the real binding constants, which still represent useful indications in the overall understanding of the systems under investigation.…”

Deciphering the Binding Insights of Novel Disubstituted Anthraquinone Derivatives with G‐Quadruplex DNA to Exhibit Selective Cancer Cell Cytotoxicity

“…The ion peaks of c‐MYC G4 DNA‐ligand complexes as 1 : 1 G4:ligand complex ratio in the ESI‐MS experiment (negative mode) indicated the stability of the G4‐compound complexes. With the ligands (APN h and APN h Me 2 ), [G4+ligand] 5− and [G4+ligand] 6− peaks are present, in addition to ion peaks from only G4 DNA (Figure 5:D–F) [54] …”

“…With the ligands (APN h and APN h Me 2 ), [G4 + ligand] 5À and [G4 + ligand] 6À peaks are present, in addition to ion peaks from only G4 DNA (Figure 5:D-F). [54]…”

Discriminating between Parallel, Anti-Parallel and Hybrid G-Quadruplexes: Mechanistic Details on Their Binding to Small Molecules

“…Many other papers cite the ability of the more different species to discriminate between G4 s forms. As for examples of parallel (c-MYC being a golden standard) G4 discrimination, we may cite benzothiazole [75], indolyl-quinolinium scaffolds [76] and pyrimidine/purine [77,78] derivatives. Telomestatin and sapphyrin cyclic heteroaryles (Figure 7a,b) deserve peculiar attention as one of the first species shown to selectively bind to a peculiar G4 (antiparallel basket-type for Figure 7a, hybrid for Figure 7b) [79].…”