Regulating Bioactivity of Cu²⁺ Bis-1,10-phenanthroline Artificial Metallonucleases with Sterically Functionalized Pendant Carboxylates

The synthetic chemical nuclease, [Cu­(1,10-phenanthroline)₂]²⁺, 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)₂]⁺, where 1,10-phen = 1,10-phenanthroline and R = −H, −CH₃, −C₂H₅, −CH­(CH₃)₂, and −C­(CH₃)₃. 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)₂]²⁺, which supports the importance of inner-sphere modification toward enhancing targeted biological application

Imidazolium and Pyridinium Ionic Liquids from Mandelic Acid Derivatives: Synthesis and Bacteria and Algae Toxicity Evaluation

A new class of low bacterial and algal toxicity imidazolium and pyridinium halide ionic liquids (ILs), produced by a short synthesis from substituted mandelic acid derivatives is disclosed. Melting points for most of the ILs were above or close to 100 °C; however, one imidazolium example has a glass transition temperature below room temperature (RT; −3.3 °C). The series of 8 ILs enables an investigation of toxicity on modifying the heterocycle, aromatic ring substitution, ester group, and proximity of cation to aromatic ring present within mandelic acid constituent. Two pyridinium salts, methyl 2-(3,4-methylenedioxyphenyl)-2-pyridinium acetate, bromide salt and methyl 2-(3,4-methylenedioxyphenyl)-2-(2-pyridiniumacetoxy)­acetate, bromide salt have low toxicity to all bacteria strains (including Vibrio fischeri), and freshwater green algae (C. Vulgaris and P. subcapitata) screened. All eight pyridinium and imidazolium ILs have low toxicity to Gram-positive (B. subtilis) and Gram-negative (E. coli, P. fluorescens, P. putida (CP1), and P. putgida (KT 2440)) bacteria strains, although a significant range in IC₅₀ values was obtained. Mandelate derived ILs have EC₅₀ (C. Vulgaris and P. subcapitata) values 10³–10⁷ higher (less toxic) than other C14–C18 ionic liquids previously reported