Regulating Bioactivity of Cu2+ Bis-1,10-Phenanthroline Artificial Metallonucleases with Sterically Functionalised Pendant Carboxylates
Prisecaru A., Mckee V., Howe O., Rochford G., McCann M, Colleran J., Barron N., Pour M., Gathergood N. and Kellett A.
Journal of Medicinal Chemistry, 56 (21), 8599-8615, 2013.
Abstract: 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.