tetracycline and 1-10-phenanthroline

This paper reports on the synthesis and characterization of two new ternary copper(II) complexes: [Cu(doxycycline)(1,10-phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (1) and [Cu(tetracycline)(1,10-phenanthroline)(H(2)O)(ClO(4))](ClO(4)) (2). These compounds exhibit a distorted tetragonal geometry around copper, which is coordinated to two bidentate ligands, 1,10-phenanthroline and tetracycline or doxycyline, a water molecule, and a perchlorate ion weakly bonded in the axial positions. In both compounds, copper(II) binds to tetracyclines via the oxygen of the hydroxyl group and oxygen of the amide group at ring A and to 1,10-phenanthroline via its two heterocyclic nitrogens. We have evaluated the binding of the new complexes to DNA, their capacity to cleave it, their cytotoxic activity, and uptake in tumoral cells. The complexes bind to DNA preferentially by the major groove, and then cleave its strands by an oxidative mechanism involving the generation of ROS. The cleavage of DNA was inhibited by radical inhibitors and/or trappers such as superoxide dismutase, DMSO, and the copper(I) chelator bathocuproine. The enzyme T4 DNA ligase was not able to relegate the products of DNA cleavage, which indicates that the cleavage does not occur via a hydrolytic mechanism. Both complexes present an expressive plasmid DNA cleavage activity generating single- and double-strand breaks, under mild reaction conditions, and even in the absence of any additional oxidant or reducing agent. In the same experimental conditions, [Cu(phen)(2)](2+) is approximately 100-fold less active than our complexes. These complexes are among the most potent DNA cleavage agents reported so far. Both complexes inhibit the growth of K562 cells with the IC(50) values of 1.93 and 2.59 μmol L(-1) for compounds 1 and 2, respectively. The complexes are more active than the free ligands, and their cytotoxic activity correlates with intracellular copper concentration and the number of Cu-DNA adducts formed inside cells.

Topics: Antineoplastic Agents; Cell Proliferation; Cell Survival; Copper; Cytotoxins; DNA Cleavage; Dose-Response Relationship, Drug; Doxycycline; Drug Screening Assays, Antitumor; Humans; K562 Cells; Molecular Conformation; Organometallic Compounds; Phenanthrolines; Stereoisomerism; Structure-Activity Relationship; Tetracycline

Tetracycline metabolites forming on the antibiotic exposure to visible light or peroxidase as well as tetracycline as such showed the ability to bind iron cations. When the metabolites bound the cations of iron protoxide, they catalyzed its oxidation. Chelating agents such as o-phenanthroline and EDTA arrested the ions of iron protoxide and iron oxide in the respective iron/tetracycline complexes at a much lower rate than that with the use of the native tetracycline. This means that the affinity of the metabolites with the above mentioned iron ions was much higher than that of the native tetracycline. When the metabolites and tetracycline bound iron protoxide, they catalyzed its oxidation to the oxide. Tetracycline and its metabolites were shown as well to have the property of reversible regeneration of iron oxide to the protoxide.

Topics: Anti-Bacterial Agents; Catalysis; Edetic Acid; Free Radicals; Horseradish Peroxidase; Iron; Iron Chelating Agents; Oxidation-Reduction; Phenanthrolines; Photochemistry; Tetracycline

Several chelators were examined for their ability to prevent the synchronous release of 24- to 48-hour stationary phase singlet cells of the dimorphic yeast Candida albicans into either the mycelial or the budding phenotypes (in a defined liquid medium at 37 degrees C; at pH 6.5 or pH 4.5, respectively). The only chelator that was found to inhibit mycelium formation completely and to restrict bud formation to about 10% was 1,10-phenanthroline at minimal concentrations of 50 microM and 230 microM, respectively. The inhibition of both phenotypes could be reversed completely by the addition of 200 microM of ZnSO4. The synchrony of recovery from inhibition by the addition of zinc paralleled that of the controls for both phenotypes, and the final number of mycelia or buds as a percentage of the control was the same (100%). These findings support the hypothesis that the lag period between the release from stationary phase and the onset of development for Candida represents the time of acquisition of a minimum threshold amount of a cation, such as zinc. The involvement of zinc in phenotypic development is discussed, suggesting that while zinc is involved in the initiation of development, it may not determine the phenotype of Candida albicans.

Topics: Candida albicans; Edetic Acid; Oxyquinoline; Pentetic Acid; Phenanthrolines; Sulfates; Tetracycline; Zinc; Zinc Sulfate