Polypyridyl‐Based Copper Phenanthrene Complexes: A New Type of Stabilized Artificial Chemical Nuclease

Abstract

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')] (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.

Copper bis-Dipyridoquinoxaline Is a Potent DNA Intercalator that Induces Superoxide-Mediated Cleavage via the Minor Groove

“…Finally, pre-treatment with the electrostatic binding agent had negligible effects (lanes 14–17). These results are in agreement with those previously reported with Cu-Phen, Cu-Phen-DPQ and Cu-TPMA-N,N′ complexes where the presence of methyl green results in enhanced chemical nuclease activity due to its minor groove priming effects [1,33,34].…”

“…In recent years, we have focused on introducing modifications to the Cu-Phen scaffold to enhance DNA recognition, oxidative damage and cytotoxicity [11]. Approaches including inner sphere modifications using coordinated carboxylate groups [13]; dicarboxylate groups (e.g., o-phthalate or octanedioate) [26,27,28,29,30,31]; designer phenazine intercalators [32,33]; tris-(2-pyridylmethyl)amine (TPMA) caging ligands [34,35]; and the introduction of a binuclear di -cation have been undertaken [26,30,36]. Previously, we reported a series of phenazine-functionalized Cu(II) phenanthroline complexes—with general formula [Cu(N,N′)(Phen)] 2+ (where N,N′ = dipyridoquinoxaline (DPQ) or dipyridophenazine (DPPZ))—that offered a significant enhancement of DNA binding affinity relative to Cu–Phen [32].…”

[Cu(TPMA)(Phen)](ClO4)2: Metallodrug Nanocontainer Delivery and Membrane Lipidomics of a Neuroblastoma Cell Line Coupled with a Liposome Biomimetic Model Focusing on Fatty Acid Reactivity

“…The EPR technique was used to investigate the structure of the free and released compounds and highlight possible modifications occurring during the encapsulation/release processes. 21 Once Cu-TPMA-Phen is released from the hollow NCs, it is necessary to verify whether its starting conformation is kept, to exert the biological activity. Figure 4 A,C shows the spectra of free Cu-TPMA-Phen dissolved in the release media in ACN/PBS (1:19) and ACN/0.1 M citrate buffer at pH 4 (1:19), respectively.…”

Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of N-alkyl-acridones and N,N′-dialkyl-9,9′-biacridylidenes

“…This experimental procedure was adapted from a method previously published elsewhere [14]. Briefly, acridones 1 – 6 and biacridylidenes 7 – 12 were initially dissolved in DMSO and further diluted in either 80 mM HEPES (pH 7.2) or 80 mM phosphate buffer (pH 5.8).…”