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Polypyridyl-Based Copper Phenanthrene Complexes: Combining Stability with Enhanced DNA Recognition.

Chemistry (Weinheim an der Bergstrasse, Germany) (2020-06-11)
Nicoló Zuin Fantoni, Zara Molphy, Sinéad O'Carroll, Georgia Menounou, George Mitrikas, Marios G Krokidis, Chryssostomos Chatgilialoglu, John Colleran, Anna Banasiak, Martin Clynes, Sandra Roche, Suainibhe Kelly, Vickie McKee, Andrew Kellett
RESUMEN

We report a series of copper(II) artificial metallo-nucleases (AMNs) and demonstrate their DNA damaging properties and in-vitro cytotoxicity against human-derived pancreatic cancer cells. The compounds combine a tris-chelating polypyridyl ligand, di-(2-pycolyl)amine (DPA), and a DNA intercalating phenanthrene unit. Their general formula is Cu-DPA-N,N' (where N,N'=1,10-phenanthroline (Phen), dipyridoquinoxaline (DPQ) or dipyridophenazine (DPPZ)). Characterisation was achieved by X-ray crystallography and continuous-wave EPR (cw-EPR), hyperfine sublevel correlation (HYSCORE) and Davies electron-nuclear double resonance (ENDOR) spectroscopies. The presence of the DPA ligand enhances solution stability and facilitates enhanced DNA recognition with apparent binding constants (Kapp ) rising from 105 to 107  m-1 with increasing extent of planar phenanthrene. Cu-DPA-DPPZ, the complex with greatest DNA binding and intercalation effects, recognises the minor groove of guanine-cytosine (G-C) rich sequences. Oxidative DNA damage also occurs in the minor groove and can be inhibited by superoxide and hydroxyl radical trapping agents. The complexes, particularly Cu-DPA-DPPZ, display promising anticancer activity against human pancreatic tumour cells with in-vitro results surpassing the clinical platinum(II) drug oxaliplatin.

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Sigma-Aldrich
Mithramycin A from Streptomyces plicatus, ≥90% (HPLC)
Sigma-Aldrich
Poly(deoxyguanylic-deoxycytidylic) acid sodium salt, double stranded, alternating copolymer