[Cu(<i>o</i>‑phthalate)(phenanthroline)] Exhibits Unique Superoxide-Mediated NCI-60 Chemotherapeutic Action through Genomic DNA Damage and Mitochondrial Dysfunction

The <i>in cellulo</i> catalytic production of reactive oxygen species (ROS) by copper­(II) and iron­(II) complexes is now recognized as a major mechanistic model in the design of effective cytotoxins of human cancer. The developmental complex, [Cu­(<i>o</i>-phthalate)­(1,10-phenanthroline)] (<b>Cu-Ph</b>), was recently reported as an intracellular ROS-active cytotoxic agent that induces double strand breaks in the genome of human cancer cells. In this work, we report the broad-spectrum action of <b>Cu-Ph</b> within the National Cancer Institute’s (NCI) Developmental Therapeutics Program (DTP), 60 human cancer cell line screen. The activity profile is compared to established clinical agentsvia the COMPARE algorithmand reveals a novel mode of action to existing metal-based therapeutics. In this study, we identify the mechanistic activity of <b>Cu-Ph</b> through a series of molecular biological studies that are compared directly to the clinical DNA intercalator and topoisomerase II poison doxorubicin. The presence of ROS-specific scavengers was employed for <i>in vitro</i> and intracellular evaluation of prevailing radical species responsible for DNA oxidation with superoxide identified as playing a critical role in this mechanism. The ROS targeting properties of <b>Cu-Ph</b> on mitochondrial membrane potential were investigated, which showed that it had comparable activity to the uncoupling ionophore, carbonyl cyanide <i>m</i>-chlorophenyl hydrazine. The induction and origins of apoptotic activation were probed through detection of Annexin V and the activation of initiator (8,9) and executioner caspases (3/7) and were structurally visualized using confocal microscopy. Results here confirm a unique radical-induced mechanistic profile with intracellular hallmarks of damage to both genomic DNA and mitochondria

Additional file 1: of Australian integrative oncology services: a mixed-method study exploring the views of cancer survivors

Focus group questionnaire and interview guide. Outline of interview schedule. (PDF 40 kb

Additional file 2: of Australian integrative oncology services: a mixed-method study exploring the views of cancer survivors

Online survey questionnaire. Survey questionnaire. (PDF 83 kb

Silver(I) complexes of 9-anthracenecarboxylic acid and imidazoles: synthesis, structure and antimicrobial activity

[Ag2(9-aca)2] (1) (9-acaH = 9-anthracenecarboxylic acid) reacts with a series of imidazoles to give [Ag(imidH)2.3(CH3CN)0.7](9-aca) (3), [Ag6(imidH)4(9-aca)6(MeOH)2] (4), {[Ag(1-Me-imid)2]2[Ag4(9- aca)6]} (5), {[Ag(1-Bu-imid)2]2[Ag4(9-aca)6]} (6) and [Ag(apim)](9-aca)·H2O (7) (imidH = imidazole; 1-Me-imid = 1-methylimidazole; 1-Bu-imid = 1-butylimidazole; apim = 1-(3-aminopropyl)imidazole). The mononuclear complex 3, hexanuclear 4–6, and polymeric 7, were all characterised using X-ray crystallography. While many of the complexes possess excellent in vitro antifungal and antibacterial activities they are, unanimously, more effective against fungal cells. The insect, Galleria mellonella, can survive high doses of the Ag(I) complexes administered in vivo, and a number of the complexes offer significant protection to larvae infected with a lethal dose of pathogenic Candida albicans cells

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