Arylsulfanyl groups - Suitable side chains for 5-substituted 1,10-phenanthroline and nickel complexes as G4 ligands and telomerase inhibitors
| Autor: | Wanbo Liu, Liang Xue, Siwen Wang, Irina A. Dotsenko, Vyacheslav V. Samoshin |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Circular dichroism Stereochemistry Metal ions in aqueous solution Phenanthroline Intercalation (chemistry) 01 natural sciences Biochemistry Inorganic Chemistry 03 medical and health sciences chemistry.chemical_compound Nickel Side chain heterocyclic compounds Enzyme Inhibitors Telomerase 010405 organic chemistry Circular Dichroism Ligand (biochemistry) Small molecule 0104 chemical sciences G-Quadruplexes 030104 developmental biology chemistry DNA Phenanthrolines |
| Zdroj: | Journal of Inorganic Biochemistry. 173:12-20 |
| ISSN: | 0162-0134 |
| DOI: | 10.1016/j.jinorgbio.2017.04.018 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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