title: Regulating bioactivity of Cu2+ bis-1,10-phenanthroline artificial metallonucleases with sterically functionalized pendant carboxylates.
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.
authors.affiliation: School of Chemical Sciences and the National Institute for Cellular Biotechnology, Dublin City University , Dublin 9, Ireland.
authors.forename: Andreea
authors.initials: A
authors.lastname: Prisecaru
authors.forename: Vickie
authors.initials: V
authors.lastname: McKee
authors.forename: Orla
authors.initials: O
authors.lastname: Howe
authors.forename: Garret
authors.initials: G
authors.lastname: Rochford
authors.forename: Malachy
authors.initials: M
authors.lastname: McCann
authors.forename: John
authors.initials: J
authors.lastname: Colleran
authors.forename: Milan
authors.initials: M
authors.lastname: Pour
authors.forename: Niall
authors.initials: N
authors.lastname: Barron
authors.forename: Nicholas
authors.initials: N
authors.lastname: Gathergood
authors.forename: Andrew
authors.initials: A
authors.lastname: Kellett
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002264:Carboxylic Acids / Q000737:chemistry; D002417:Cattle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003300:Copper / Q000737:chemistry; D004247:DNA / Q000187:drug effects* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006090:Gram-Negative Bacteria / Q000187:drug effects*; D006094:Gram-Positive Bacteria / Q000187:drug effects*; D006801:Humans; D008826:Microbial Sensitivity Tests; D008958:Models, Molecular; D015394:Molecular Structure; D009942:Organometallic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D010618:Phenanthrolines / Q000737:chemistry; D012709:Serum Albumin / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000900:Anti-Bacterial Agents; D002264:Carboxylic Acids; D009942:Organometallic Compounds; D010618:Phenanthrolines; D012709:Serum Albumin; D003300:Copper; D004247:DNA; C427203:calf thymus DNA; C025205:1,10-phenanthroline