Regulating Bioactivity of
Cu<sup>2+</sup> Bis-1,10-phenanthroline
Artificial Metallonucleases with Sterically Functionalized Pendant
Carboxylates
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Abstract
The
synthetic chemical nuclease, [Cu(1,10-phenanthroline)<sub>2</sub>]<sup>2+</sup>, has stimulated research within metallonuclease development
and in the area of cytotoxic metallodrug design. Our analysis reveals,
however, that this agent is “promiscuous” as it binds
both dsDNA and protein biomolecules, without specificity, and induces
general toxicity to a diversity of cell lineages. Here, we describe
the synthesis and characterization of small-molecule metallonucleases
containing the redox-active cation, [Cu(RCOO)(1,10-phen)<sub>2</sub>]<sup>+</sup>, where 1,10-phen = 1,10-phenanthroline and R = −H,
−CH<sub>3</sub>, −C<sub>2</sub>H<sub>5</sub>, −CH(CH<sub>3</sub>)<sub>2</sub>, and −C(CH<sub>3</sub>)<sub>3</sub>.
The presence of coordinated carboxylate groups in the complex cation
functions to enhance dsDNA recognition, reduce serum albumin binding,
and offer control of toxicity toward human cancer cells, Gram positive
and negative bacteria, and fungal pathogens. The induction of genomic
dsDNA breaks (DSBs) were identified in ovarian adenocarcinoma cells
using immunodetection of γ-H2AX. Formate, acetate, and pivalate
functionalized complexes induced DSBs in a higher percentage of cells
compared with [Cu(1,10-phen)<sub>2</sub>]<sup>2+</sup>, which supports
the importance of inner-sphere modification toward enhancing targeted
biological application