期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 25, 期 1, 页码 221-237出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201804084
关键词
chemical nuclease; copper; DNA damage; DNA repair; phenazine
资金
- Marie Sklodowska-Curie Innovative Training Network (ITN) ClickGene [H2020-MSCA-ITN-2014-642023]
- Science Foundation Ireland Career Development Award (SFI-CDA) [15/CDA/3648]
- Carlsberg Foundation [CF15-0675]
- Programme for Research in Third Level Institutions (PRTLI) Cycle 5
- European Regional Development Fund (ERDF), part of the European Union Structural Funds Programme 2011-2015
- Operational Programme Competitiveness, Entrepreneurship and Innovation [MIS 5002567]
- Greece and the European Union (European Regional Development Fund)
The building of robust and versatile inorganic scaffolds with artificial metallo-nuclease (AMN) activity is an important goal for bioinorganic, biotechnology, and metallodrug research fields. Here, a new type of AMN combining a tris-(2-pyridylmethyl)amine (TPMA) scaffold with the copper(II) N,N '-phenanthrene chemical nuclease core is reported. In designing these complexes, the stabilization and flexibility of TPMA together with the prominent chemical nuclease activity of copper 1,10-phenanthroline (Phen) were targeted. A second aspect was the opportunity to introduce designer phenazine DNA intercalators (e.g., dipyridophenazine; DPPZ) for improved DNA recognition. Five compounds of formula [Cu(TPMA)(N,N ')](2+) (where N,N ' is 2,2-bipyridine (Bipy), Phen, 1,10-phenanthroline-5,6-dione (PD), dipyridoquinoxaline (DPQ), or dipyridophenazine (DPPZ)) were developed and characterized by X-ray crystallography. Solution stabilities were studied by continuous-wave EPR (cw-EPR), hyperfine sublevel correlation (HYSCORE), and Davies electron-nuclear double resonance (ENDOR) spectroscopies, which demonstrated preferred geometries in which phenanthrene ligands were coordinated to the copper(II) TPMA core. Complexes with Phen, DPQ, and DPPZ ligands possessed enhanced DNA binding activity, with DPQ and DPPZ compounds showing excellent intercalative effects. These complexes are effective AMNs and analysis with spin-trapping scavengers of reactive oxygen species and DNA repair enzymes with glycosylase/endonuclease activity demonstrated a distinctive DNA oxidation activity compared to classical Sigman- and Fenton-type reagents.
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