G-Quadruplex Recognition by Quinacridines: a SAR, NMR, and Biological Study

• Published in: ChemMedChem Vol. 2; no. 5; pp. 655 - 666
• Main Authors: Hounsou, Candide, Guittat, Lionel, Monchaud, David, Jourdan, Muriel, Saettel, Nicolas, Mergny, Jean-Louis, Teulade-Fichou, Marie-Paule
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 14.05.2007; WILEY‐VCH Verlag; Wiley-VCH Verlag
• Subjects: Acridines - chemistry; Chemical Sciences; DNA structures; electrostatic interactions; Fluorescence Resonance Energy Transfer; Magnetic Resonance Spectroscopy; NMR spectroscopy; Organic chemistry; quinacridines; stacking interactions; Structure-Activity Relationship
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.200600286

The synthesis of a novel group of quinacridine‐based ligands (MMQs) is described along with an evaluation of their G‐quadruplex binding properties. A set of biophysical assays was applied to characterize their interaction with DNA quadruplexes: FRET–melting experiments and equilibrium microdialysis were used to evaluate their quadruplex affinity and their ability to discriminate quadruplexes across a broad panel of DNA structures. All data collected support the proposed model of interaction of these compounds with G‐quadruplexes, which is furthermore confirmed by a solution structure determined by 2D NMR experiments. Finally, the activity of the MMQ series against tumor cell growth is reported, and the data support the potential of quadruplex‐interactive compounds for use in anticancer approaches. The synthesis and evaluation of G‐quadruplex binding properties of a series of quinacridine‐based ligands (MMQs) are described. Structure–activity relationship studies support a model of interaction of these compounds with G‐quadruplex structures which is furthermore confirmed by the solution structure determined by 2D NMR experiments.