Metal complexes as potential ligands : the deprotonation of aminephenolate metal complexes

The cationic nickel, copper and zinc complexes of tris-(2-hydroxybenzyl)-aminoethylamine (H6TrenSal) have been deprotonated using potassium hydroxide. The nickel complex can be sequentially deprotonated to form a series of compounds namely, [(H6TrenSal)Ni]+, [(H6TrenSal)Ni] and "[(H6TrenSal)Ni]K". The latter is isolated as a mixture of species namely [{(H6TrenSal)Ni}K(EtOH)]2, [{(H6TrenSal)Ni}K(EtOH)2-μ-OH2]2 and [{(H6TrenSal)Ni}K(EtOH)2-μ-EtOH]2, which co-crystallise in a roughly 50:27.5:22.5 ratio. In contrast the deprotonation of [(H6TrenSal)M]+ (M = Cu, Zn) results in the formation of tetrameric complexes [({(H6TrenSal)Ni}K(OH2)2)4(μ4-OH2)]

Schiff base complexes of copper and zinc as potential anti-colitic compounds

The design, synthesis and activity of polymodal compounds for the treatment of inflammatory bowel disease are reported. The compounds, being based on a metal-Schiff base motif, are designed to degrade during intestinal transit to release the bioactive components in the gut. The compounds have been developed sequential with the biomodal compounds combining copper or zinc with a salicylaldehyde adduct. These compounds were tested in a formalin induced colonic inflammation model in BK:A mice. From these studies a trimodal compound based on a zinc Schiff base analogue of Sulfosalazine were designed. This was tested against a trinitrobenzenesulfonic acid (TNB) induced colitic model in Wistar rats. The use of two models allows us to test our compounds in both an acute and a chronic model. The trimodal compound reported is observed to provide anticolitic properties in the chronic TNB induced colitis model commensurate with that of SASP. However, the design of trimodal compound still has the capacity for further development. This the platform reported may offer a route into compounds which can markedly outperform the anti-colitic properties of SASP

Tetradentate Schiff base beryllium complexes

The structure of (BeSalen)2 is reported. The incompatibility of the geometry of the beryllium with the inflexibility of the Salen ligand gives rise to a rare dimeric bis-didentate motif

Determination of metal ion concentrations by SERS using 2,2’-bipyridyl complexes

Surface enhanced Raman scattering (SERS) can generate characteristic spectral “fingerprints” from metal complexes, thus providing the potential for the development of methods of analysis for the identification and quantitation of a range of metal ions in solution. The advantages include sensitivity and the use of one ligand for several metals without the need for a specific chromophore. Aqueous solutions of Fe(II), Ni(II), Zn(II), Cu(II), Cr(III) and Cd(II) in the presence of excess 2,2′-bipyridyl (bipy) were analysed using SERS. Specific marker bands enabled the identification of each metal ion and the limit of detection for each metal ion was estimated. Two of the ions, Zn(II) and Cu(II), could be detected below the World Health Organisation's (WHO) recommended limits for drinking water at levels of 0.22 and 0.6 mg L−1, respectively

Detection of potentially toxic metals by SERS using salen complexes

Surfaced enhanced Raman scattering (SERS) can discriminate between metal complexes due to the characteristic “spectral fingerprints” obtained. As a result, SERS has the potential to develop relatively simple and sensitive methods of detecting and quantifying a range of metal ions in solution. This could be beneficial for the environmental monitoring of potentially toxic metals (PTMs). Here, salen (C16H16N2O2) was used as a ligand to form complexes of Ni(II), Cu(II), Mn(II) and Co(II) in solution. The SERS spectra showed characteristic spectral differences specific to each metal complex, thus allowing the identification of each of these metal ions. This method allows a number of metal ions to be detected using the same ligand and an identical preparation procedure. The limit of detection (LOD) was determined for each metal ion, and it was found that Ni(II), Cu(II) and Mn(II) could be detected below the WHO’s recommended limits in drinking water at 1, 2 and 2 µg L-1, respectively. Co(II) was found to have an LOD of 20 µg L-1, however no limit has been set for this ion by the WHO as the concentration of Co(II) in drinking water is generally <1-2 μg L-1. A contaminated water sample was also analysed where Mn(II) was detected at a level of 800 µg L-1

Identification of two new core chromosome-encoded superantigens in Streptococcus pyogenes; speQ and speR

Superantigens are ubiquitous within the Streptococcus pyogenes genome, which suggests that superantigen-mediated T-cell activation provides a significant selective advantage. S. pyogenes can carry a variable complement of the 11 known superantigens. We have identified two novel S. pyogenes superantigens, denoted speQ and speR, adjacent to each other in the core-chromosome of isolates belonging to eleven different emm-types. Although distinct from other superantigens, speQ and speR were most closely related to speK and speJ respectively. Recombinant SPEQ and SPER were mitogenic towards human peripheral blood mononuclear cells at ng/ml concentrations, and SPER was found to be more mitogenic than SPEQ

Highly selective identification of novel vaccine candidate antigens by immunoprecipitation: the group A streptococcal case

Streptococcus pyogenes (group A streptococcus, GAS) is an obligate human pathogen that causes a spectrum of pathologies ranging from superficial infections of the skin and oropharynx to severe invasive infections of the soft tissues. Despite a steady rise in the global rate of severe GAS disease over the past 30 years, there is currently no licenced vaccine available for the prevention of GAS infection. The initial stages of GAS pathogenesis are mediated by a repertoire of proteinaceous virulence factors expressed on the bacterial cell surface that facilitate colonisation and infection through specific interactions with the host extracellular matrix. These proteins are therefore predisposed to recognition by the host immune system, which in turn makes them important targets for the development of a novel subunit vaccine. The thesis describes the development of a novel approach to the isolation and identification of the major surface antigens of GAS using twenty GAS isolates representing four serotypes actively circulating within the United Kingdom (M1, M3, M12 and M89). Antigens were purified by immunoprecipitation using an antibody formulation derived from the human clinical blood product IVIG which has been shown to protect against severe GAS infection both clinically and in vivo. This “enriched” (E-)IVIG was produced by affinity purification using a concentrated GAS cell wall protein fraction and was shown to promote neutrophil uptake in an ex vivo opsonophagocytosis assay, and impair dissemination of GAS from the nidus of infection in a murine model. A total of eight pan-serotype vaccine candidate antigens were identified by E-IVIG immunoprecipitation, seven of which were produced recombinantly for use in murine vaccination experiments. This novel approach to vaccine candidate identification could be applied to other gram positive pathogens including Staphylococcus aureus, and may have wider implications for the field of bacterial vaccinology as a whole.Open Acces

The accessory protein TagV is required for full Type VI secretion system activity in <i>Serratia marcescens</i>

The bacterial Type VI secretion system (T6SS) is a dynamic macromolecular structure that promotes inter- and intra-species competition through the delivery of toxic effector proteins into neighbouring cells. The T6SS contains 14 well-characterised core proteins necessary for effector delivery (TssA-M, PAAR). In this study, we have identified a novel accessory component required for optimal T6SS activity in the opportunistic pathogen Serratia marcescens, which we name TagV. Deletion of tagV, which encodes an outer membrane lipoprotein, caused a reduction in the T6SS-dependent antibacterial activity of S. marcescens Db10. Mutants of S. marcescens lacking the core component TssJ, a distinct outer membrane lipoprotein previously considered essential for T6SS firing, retained a modest T6SS activity that could be abolished through deletion of tagV. TagV did not interact with the T6SS membrane complex proteins TssL or TssM, but is proposed to bind to peptidoglycan, indicating that the mechanism by which TagV promotes T6SS firing differs from that of TssJ. Homologues of tagV were identified in several other bacterial genera, suggesting that the accessory function of TagV is not restricted to S. marcescens. Together, our findings support the existence of a second, TssJ-independent mechanism for T6SS firing that is dependent upon the activity of TagV proteins.</p

A study of the nitroprusside anion and some of its analogues

Sodium nitroprusside is a potent vasodilator and is widely used for lowering the blood pressure during major surgery. The physiological response is said to occur due to a nitrosation reaction at the smooth muscle membrane. The use of sodium nitroprusside has been restricted due to its ability' to release toxic cyanide in-vivo and in-vitro, which can cause severe complications during surgery. Chapter one is a study of the aqueous chemistry of sodium nitroprusside with amines and thiols. It is shown that steric factors play an important role and that thiols are more reactive than amines. The information is used to evaluate the chemical changes expected at the smooth muscle membrane and possible mechanisms for biochemical action. If the toxicity of nitroprusside anion cannot be aleviated the information can be used to evaluate the potential of other inorganic complexes as potential hypertensive agents. Chapter two deals with the biochemical and medical problems associated with sodium nitroprusside therapy. The interaction of the complex with human erytthrocytes is explored and the reasons for cyanide release are discussed. The toxicity associated with the complex is shown to be impossible to eradicate completely and short term measures to minimise the effects are given. Chapter three explores the implications of the nitrosyl stretching frequency and how its value could be used to indicate whether a compound would be expected to exhibit nitroprusside-type chemistry. The reactivity of five nitrosylpentacyanometallates with the simple reagents previously discussed in chapter one are investigated to show that the nitrosyl group can be positive, neutral or negative and that this information could be easily acquired from the stretching frequency of the nitrosyl group in the infra-red. A value for the nitrosyl stretching frequency is given, above which a compound would be expected to exhibit nitroprusside-type chemistry. These compounds would be expected to be vasodilators