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Forty Years after the Discovery of Its Nucleolytic Activity: [Cu(phen)₂ ]²⁺ Shows Unattended DNA Cleavage Activity upon Fluorination.

ABSTRACT: [Cu(phen)₂ ]²⁺ (phen=1,10-phenanthroline) is the first and still one of the most efficient artificial nucleases. In general, when the phen ligand is modified, the nucleolytic activity of its Cu^II complex is significantly reduced. This is most likely due to higher steric bulk of such ligands and thus lower affinity to DNA. Cu^II complexes with phen ligands having fluorinated substituents (F, CF₃ , SF₅ , SCF₃ ) surprisingly showed excellent DNA cleavage activity-in contrast to the unsubstituted [Cu(phen)₂ ]²⁺ -in the absence of the otherwise required classical, bioabundant external reducing agents like thiols or ascorbate. This nucleolytic activity correlates well with the half-wave potentials E_1/2 of the complexes. Cancer cell studies show cytotoxic effects of all complexes with fluorinated ligands in the low μm range, whereas they were less toxic towards healthy cells (fibroblasts).

SUBMITTER: Ludtke C

PROVIDER: S-EPMC7898652 | biostudies-literature | 2021 Feb

REPOSITORIES: biostudies-literature

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Forty Years after the Discovery of Its Nucleolytic Activity: [Cu(phen)2 ]2+ Shows Unattended DNA Cleavage Activity upon Fluorination.

Lüdtke Carsten C Sobottka Sebastian S Heinrich Julian J Liebing Phil P Wedepohl Stefanie S Sarkar Biprajit B Kulak Nora N

Chemistry (Weinheim an der Bergstrasse, Germany) 20210122 10

[Cu(phen)2 ]2+ (phen=1,10-phenanthroline) is the first and still one of the most efficient artificial nucleases. In general, when the phen ligand is modified, the nucleolytic activity of its CuII complex is significantly reduced. This is most likely due to higher steric bulk of such ligands and thus lower affinity to DNA. CuII complexes with phen ligands having fluorinated substituents (F, CF3 , SF5 , SCF3 ) surprisingl ...[more]

PMID: 33245157

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Project description:Copper-dependent metalloenzymes are widespread throughout metabolic pathways, coupling the reduction of O2 with the oxidation of organic substrates. Small-molecule synthetic analogs are useful platforms to generate L/Cu/O2 species that reproduce the structural, spectroscopic, and reactive properties of some copper-/O2-dependent enzymes. Landmark studies have shown that the conversion between dicopper(II)-peroxo species (L2CuII2(O22-) either side-on peroxo, SP, or end-on trans-peroxo, TP) and dicopper(III)-bis(μ-oxo) (L2CuIII2(O2-)2: O) can be controlled through ligand design, reaction conditions (temperature, solvent, and counteranion), or substrate coordination. We recently published ( J. Am. Chem. Soc. 2012 , 134 , 8513 , DOI: 10.1021/ja300674m ) the crystal structure of an unusual SP species [(MeAN)2CuII2(O22-)]2+ (SPMeAN, MeAN: N-methyl-N,N-bis[3-(dimethylamino)propyl]amine) that featured an elongated O-O bond but did not lead to O-O cleavage or reactivity toward external substrates. Herein, we report that SPMeAN can be activated to generate OMeAN and perform the oxidation of external substrates by two complementary strategies: (i) coordination of substituted sodium phenolates to form the substrate-bound OMeAN-RPhO- species that leads to ortho-hydroxylation in a tyrosinase-like fashion and (ii) addition of stoichiometric amounts (1 or 2 equiv) of Lewis acids (LA's) to form an unprecedented series of O-type species (OMeAN-LA) able to oxidize C-H and O-H bonds. Spectroscopic, computational, and mechanistic studies emphasize the unique plasticity of the SPMeAN core, which combines the assembly of exogenous reagents in the primary (phenolates) and secondary (Lewis acids association to the MeAN ligand) coordination spheres with O-O cleavage. These findings are reminiscent of the strategy followed by several metalloproteins and highlight the possible implication of O-type species in copper-/dioxygen-dependent enzymes such as tyrosinase (Ty) and particulate methane monooxygenase (pMMO).

Dataset Information

Forty Years after the Discovery of Its Nucleolytic Activity: [Cu(phen)₂ ]²⁺ Shows Unattended DNA Cleavage Activity upon Fluorination.

Publications

Forty Years after the Discovery of Its Nucleolytic Activity: [Cu(phen)<sub>2</sub> ]<sup>2+</sup> Shows Unattended DNA Cleavage Activity upon Fluorination.

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