Exposure to caspofungin activates Cap and Hog pathways in Candida albicans.

Caspofungin is a member of the echinocandin group of antifungals and inhibits the activity of B-glucan synthase thus disrupting cell wall formation and function. While the potent antifungal activity of this agent is well established, this paper analyzed the response of Candida albicans to caspofungin. Exposure of yeast cells to 0.19 μg/ml caspofungin for 1 to 4 h induced nuclear translocation of Cap1p which was confirmed by Western blotting and confocal microscopy. Caspofungin-treated cells demonstrated increased expression of a number of genes associated with the oxidative stress response, including glutathione reductase (GLR1), mitochondrial processing protease (MAS1) and manganese-superoxide dismutase (SOD2) as well as elevated activity of glutathione reductase and superoxide dismutase. Caspofungin treatment also leads to the nuclear localization of Hog1p as visualized by Western blot using anti-phospho-p38 MAPK (Thr180/Tyr182) antibody. This translocation event lead to increased mRNA levels of catalase (CAT1) but not alkyl hydroperoxide reductase (AHP1). The activity of catalase was increased and reached a maximum at 2 h. In addition, pre-exposure of C. albicans to hydrogen peroxide (0.5 mM, 60 min) conferred an increased tolerance to caspofungin. The data presented here highlight the potent antifungal activity of caspofungin and demonstrate that upon exposure to this agent, C. albicans activates the Cap and Hog pathways in an attempt to limit the oxidative and osmotic stresses associated with this drug

Mixtures obtained by reacting trans-(�)-1,2diaminocyclohexane with acetylacetone in the presence of simple cobalt(II) salts.

In the absence of a metal ion, racemic trans-1,2-diaminocyclohexane (trans-(�)DCH) reacts with acetylacetone (acacH) (1:2.5 mole ratio) to form the bisoxoenamine condensation product, boe (1). CoCl2·6H2O and Co(ClO4)2·6H2O each react with trans-(�)DCH in air to give complexes containing the oxidised Co(III) ion, [Co((�)DCH)3]3+, which does not subsequently react with added acacH to give a Schiff base complex. Mixtures of complexes are obtained from one-pot reactions involving trans-(�)DCH, a simple Co(II) salt and acacH (1:1:2.5 mole ratio). When CoCl2·6H2O is used, the mixed-ligand Co(II) complex [Co((�)DCH)Cl2] (4) precipitates first and, after a period of weeks, the Co(II) complex (diazH)2[CoCl4] (5) (diazH+ is a diazepinium cation), the Co(II) complex [Co(boe)Cl2]n (6) and the Co(III) complex [Co(acac)3] (7), co-crystallise from the mother liquor. Using Co(ClO4)2·6H2O in the reaction with trans-(�)DCH and acacH also gives a mixture of products. Complexes 7, the Co(II) complex [Co2(acac)4(H2O)2][Co(acac)(H2O)4]ClO4·EtOH (8) and the Co(III) complex [Co(acac)2(�)DCH]ClO4 (9) co-crystallise. Complexes 1, 5, 7, 8 and 9 were characterised using X-ray crystallography. The major difference between using CoCl2·6H2O and Co(ClO4)2·6H2O in reactions involving (�)DCH and acacH is that no DCH/acacH condensation products are identified in the product mixtures when the perchlorate salt is employed

Metal complexes of 1,10-phenanthroline-5,6-dione alter the susceptibility of the yeast Candida albicans to Amphotericin B and Miconazole

Growth of the pathogenic yeast Candida albicans in sub-MIC (minimum inhibitory concentration) levels of Cu(ClO4)2 · 6H2O and [Cu(phendio)3](ClO4)2 · 4H2O (phendio = 1,10-phenanthroline-5,6-dione) increased the concentration of miconazole and amphotericin B required to achieve the MIC90 whereas pre-growth in AgClO4 and [Ag(phendio)2]ClO4 resulted in a small decrease in the relevant MIC90 values. The copper complexes reduce the oxygen consumption of C. albicans while the silver complexes increase oxygen consumption. In addition, pregrowth of cells in the copper complexes resulted in a lower ergosterol content while the silver complexes induced an elevation in ergosterol synthesis. The ability of copper and silver complexes to alter the susceptibility of C. albicans to miconazole and amphotericin B may be influenced by their action on respiration, since reduced respiration rates correlate with reduced cellular ergosterol which is the target for amphotericin B. Lower levels of ergosterol have previously been associated with elevated tolerance to this drug. In the case of reduced sensitivity to miconazole, tolerance may be mediated by lower ergosterol synthesis giving rise to fewer toxic side products once biosynthesis is inhibited by miconazole

In vitro anti-tumour effect of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 using human epithelial cell lines.

The anti-cancer chemotherapeutic potential of 1,10-phenanthroline-5,6-dione (phendione), [Cu(phendione)3](ClO4)2·4H2O and [Ag(phendione)2]ClO4 were determined using four human cells lines, i.e. two neoplastic (A-498 and Hep-G2) and two non-neoplastic (CHANG and HK-2). All of the phendione derivatives induced a concentration-dependant decrease in the viability of the four cell lines, with [Cu(phendione)3](ClO4)2·4H2O displaying greatest activity. In comparative studies, IC50 values obtained with the two neoplastic cell lines showed a cytotoxic response which was between 3 and 35 times greater than that observed for the metal-based anti-cancer agent, cisplatin. Furthermore, metal–phendione complexes, rather than simple solvated metal ions, were responsible for the observed cytotoxicity. Despite the high level of potency associated with these compounds they did not display an apparent cyto-selective profile, as they reduced the viability of both neoplastic and non-neoplastic cells. However, selected mechanistic studies showed that phendione and its metal complexes inhibited DNA synthesis which did not appear to be mediated through intercalation. Ames testing highlighted that all three compounds and their phase I metabolites were non-mutagenic, unlike cisplatin. Taken together, these results suggest that phendione and its Cu(II) and Ag(I) complexes may be capable of acting as highly effective anti-cancer therapies, which with careful administration could provide very potent and effective alternatives to cisplatin

Encapsulated Dicopper(I): Kinetic or Thermodynamic Stabilization?

Cyclic voltammetry of a series of air-stable dicopper(I.I) azacryptates indicates that some, including those with heterocyclic-N-donor spacers, are thermodynamically unstable towards oxidation by O2; in this case outer-sphere oxidation by Fc+ or Ag+ is readily achieved

The Antibacterial Activity of Metal Complexes Containing 1, 10-phenanthroline: Potential as Alternatire Therapeutics in the Era of Antibiotic Resistance

The “antibiotic era”, characterized by the overuse and misuse of antibiotics, over the last half-century has culminated in the present critical “era of resistance”. The treatment of bacterial infections is challenging because of a decline in the current arsenal of useful antibiotics and the slow rate of new drug development. The discovery of a new gene (mcr-1) in 2015, which enables bacteria to be highly resistant to polymyxins (such as colistin), the last line of antibiotic defence left, heralds a new level of concern as this gene is susceptible to horizontal gene transfer, with alarming potential to be spread between different bacterial populations, suggesting that the progression from “extensive drug resistance” to “pan-drug resistance” may be inevitable. Clearly there is a need for the development of novel classes of anti-bacterial agents capable of killing bacteria through mechanisms that are different to those of the known classes of antibiotics. 1,10-phenanthroline (phen) is a heterocyclic organic compound which exerts in vitro antimicrobial activity against a broad-spectrum of bacteria. The antimicrobial activity of phen can be significantly modulated by modifying its structure. The development of metal-phen complexes offers the medicinal chemist an opportunity to expand such structural diversity by controlling the geometry and varying the oxidation states of the metal centre, with the inclusion of appropriate auxiliary ligands in the structure, offering the opportunity to target different biochemical pathways in bacteria. In this review, we summarize what is currently known about the antibacterial capability of metal-phen complexes and their mechanisms of action

Synthesis and catalase activity of manganese (ii) complexes of cis-5-norbornene-endo-2, 3-dicarboxylic acid (ndaH2): x-ray crystal structure of [Mn(qb11-nda)(phen)2]• EtOH'H20\ud (phen = 1,10-phenanthroline)

Manganese(II) chloride reacts with the sodium salt of cis-5-norbornene-endo- 2,3-dicarboxylic acid (ndaH2) in aqueous media to give the manganese(II) complex [Mn (nda)H20] (1). Complex 1 reacts with 1,10-phenanthroline (phen) to give the mononuclear manganese(II) adduct [Mn(~/lql-nda)(phen)2] • EtOH" H20 (2). The X-ray crystal structure of 2 shows the manganese atom at the centre of a distorted N402 octahedron comprising four nitrogen atoms from two chelating phen ligands, and two oxygen atoms, one from each of the two carboxylate functions of the nda 2- ligand. Spectroscopic and magnetic data for 1 and 2 are reported, together with their catalytic activity towards the disproportionation of H202

In vitro cancer chemotherapeutic activity of 1,10-phenanthroline (phen), [Ag2(phen)3(mal)] Æ 2H2O, [Cu(phen)2(mal)] Æ 2H2O and [Mn(phen)2(mal)] Æ 2H2O (malH2 = malonic acid) using human cancer cells.

The chemotherapeutic potential of 1,10-phenanthroline (phen), and three of its transition metal complexes, namely [Cu(phen)2(mal)] Æ 2H2O, [Mn(phen)2(mal)] Æ 2H2O and [Ag2(phen)3(mal)] Æ 2H2O (malH2 = malonic acid) was determined using two human carcinoma cell lines (A-498 and Hep-G2). Phen and the three metal–phen complexes induced a concentration- dependent cytotoxic effect, with metal complexes demonstrating the greatest cytotoxic response. In comparative studies, IC50 values show cytotoxicity of between 3 and 18 times greater than that observed for the metal-based anti-cancer agent, cisplatin. All of the phen-based complexes inhibited DNA synthesis which did not appear to be mediated through intercalation. Also, the potential cancer chemotherapeutic application of these compounds was seen to be enhanced by results obtained from Ames tests, which showed all of the test agents and their phase I metabolites were non-mutagenic. Taken together, these results suggest that phen and the three metal–phen complexes may have a therapeutic role to play in the successful treatment and management of cancer

Silver(I) and Copper(II) Complexes of 1,10-Phenanthroline-5,6-Dione Against Phialophora Verrucosa: A Focus on the Interaction With Human Macrophages and Galleria Mellonella Larvae

Phialophora verrucosa is a dematiaceous fungus that causes mainly chromoblastomycosis, but also disseminated infections such as phaeohyphomycosis and mycetoma. These diseases are extremely hard to treat and often refractory to current antifungal therapies. In this work, we have evaluated the effect of 1,10-phenanthroline-5,6-dione (phendione) and its metal-based complexes, [Ag (phendione)2]ClO4 and [Cu(phendione)3](ClO4)2.4H2O, against P. verrucosa, focusing on (i) conidial viability when combined with amphotericin B (AmB); (ii) biofilm formation and disarticulation events; (iii) in vitro interaction with human macrophages; and (iv) in vivo infection of Galleria mellonella larvae. The combination of AmB with each of the test compounds promoted the additive inhibition of P. verrucosa growth, as judged by the checkerboard assay. During the biofilm formation process over polystyrene surface, sub-minimum inhibitory concentrations (MIC) of phendione and its silver(I) and copper(II) complexes were able to reduce biomass and extracellular matrix production. Moreover, a mature biofilm treated with high concentrations of the test compounds diminished biofilm viability in a concentration-dependent manner. Pre-treatment of conidial cells with the test compounds did not alter the percentage of infected THP-1 macrophages; however, [Ag(phendione)2]ClO4 caused a significant reduction in the number of intracellular fungal cells compared to the untreated system. In addition, the killing process was significantly enhanced by post-treatment of infected macrophages with the test compounds. P. verrucosa induced a typically cell density-dependent effect on G. mellonella larvae death after 7 days of infection. Interestingly, exposure to the silver(I) complex protected the larvae from P. verrucosa infection. Collectively, the results corroborate the promising therapeutic potential of phendione-based drugs against fungal infections, including those caused by P. verrucosa

Is the C=O frequency shift a reliable indicator of coumarin binding to metal ions through the carbonyl oxygen?

The coumarin ligand, 4-hydroxy-3-nitro-2H-chromen-2-one (Hhnc) and its Cu(II) and Ag(I) complexes were studied by DFT calculations at B3LYP/B1 and PW91/B1 levels. MEP of the deprotonated ligand, hnc-, and energy calculations of model metal complexes predicted the ligand binding to the metal ion through the hydroxyl and the nitro oxygens in agreement with experiment. Based on precisely selected Cu/Ag model complexes with hnc-, a relation between the vibrational behaviour of the ligand donor groups and the ligand binding modes in the complexes was deduced. The observed carbonyl m(C=O) downshift (50–90 cm-1) is attributed to intermolecular H-bonding formed between the C@O group and lattice water molecules or due to the C@O binding to the metal ion in case of bridging coumarin ligand (in Aghnc). Much larger m(C=O) downshift (~220–240 cm-1) is predicted in case of monodentate or bidentate (with the nitro group) bonding of the carbonyl C=O group to the metal ion