Arylsulfanyl groups - Suitable side chains for 5-substituted 1,10-phenanthroline and nickel complexes as G4 ligands and telomerase inhibitors

• Published in: Journal of inorganic biochemistry 2017-08, Vol.173, p.12-20
• Main Authors: Liu, Wanbo, Wang, Siwen, Dotsenko, Irina A., Samoshin, Vyacheslav V., Xue, Liang
• Format: Article
• Language: English
• Subjects: Circular Dichroism; DNA binding ligands; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; G-quadruplex DNA; G-Quadruplexes - drug effects; Nickel - chemistry; Phenanthroline; Phenanthrolines - chemistry; Telomerase - antagonists & inhibitors; Telomerase inhibition
• ISSN: 0162-0134; 1873-3344
• DOI: 10.1016/j.jinorgbio.2017.04.018

Guanine-rich DNA sequences can undergo self-assembly into unique G-quadruplex structures that interfere with the binding of proteins to the same DNA region. The formation of DNA G-quadruplexes requires monovalent cations (Na+ and K+) or small molecules known as G-quadruplex (G4) ligands. Phenanthroline is a type of G4 ligand scaffold known for its coordination with metal ions to form complexes with a large aromatic surface area, which aptly stack with G-quartets. In this report, we have investigated the side chain effect on G-quadruplex recognition by evaluating a series of 5-substituted phenanthroline-based metal complexes (Phen-Ni) binding to telomeric G-quadruplex DNA. Results from biophysical methods including fluorescence and circular dichroism (CD) thermal denaturation, CD titration, and the fluorescent intercalator displacement (FID) assay suggest that several Phen-Ni complexes bind to G-quadruplex DNA with submicromolar G4DC50 values. Arylsulfanyl groups at the 5 position of 1,10-phenanthroline are the best side chains regarding binding affinity and selectivity towards G-quadruplex DNA. Most of the G-quadruplex binding Phen-Ni complexes can inhibit telomerase activity in vitro as indicated by the telomeric repeat amplification protocol (TRAP) assay and such inhibition is clearly concentration dependent. Our results here provide a guidance of utilizing 5-substituted phenanthroline derivatives as a viable and facile approach to design novel G4 ligands. 5-substituted phenanthroline and Ni2+ complexes as good G-quadruplex (G4) ligands and telomerase inhibitors. [Display omitted] •Ni2+ is crucial for complexes to bind to G-quadruplex DNA.•Complexes induce G-quadruplex formation under Na+ and K+ deficient conditions.•Several complexes exhibit submicromolar concentrations in the FID assay.•Arylsulfanyl groups are good side chains for complexes as G-quadruplex ligands.•Inhibition of telomerase activity by complexes is concentration dependent.