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)]

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

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

Coinage metal complexes of a boron substituted soft scorpionate ligand

An improved synthesis of lithium phenyltris(methimazolyl)borate, Li[PhTm(Me)], (methimazole = 1-methylimidazole-2-thione) is described, and the structure of the methanol-solvated [Li(OHMe)4][PhTm(Me)] has been determined. The syntheses and characterization of complexes [M(PhTm(Me))(PR3)] (M = Cu, Ag, Au; R = Et, Ph;) are reported, and the complexes [Cu(PhTm(Me))(PPh3)], [Ag(PhTm(Me))(PEt3)] and [Au(PhTm(Me))(PEt3)] are crystallographically characterized, showing a progression from pseudo-tetrahedral geometry (copper, S3P coordination) to trigonal planar geometry (silver, S2P coordination) to linear geometry (gold, SP coordination). In addition, the copper(I) and silver(I) triphenylphosphine complexes of the adventitiously formed phenylhydrobis(methimazolyl)borate ligand, [M(PhBm(Me))(PPh3)], have been crystallographically characterized, showing both species to have a trigonal planar primary coordination sphere, with a secondary M...H-B interaction. Finally, reaction of copper(II) chloride with Li[PhTm(Me)] results in formation of a compound analyzing as [Cu(II)(PhTm(Me))Cl], although its extreme insolubility and marked instability have precluded its complete characterization. Attempts to prepare this by ultra-slow diffusion of the reactants through solvent blanks has led to isolation of a mixed-valence copper(I/II) methimazolate cluster, [Cu(I)10Cu(II)2(mt)12Cl2] and a copper(I) dimeric complex [Cu2(PhTm(Me))2], indicating that copper(II) ions oxidatively decompose the phenyltris(methimazolyl)borate anion

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

Studies of oxidative stress in cellular systems The interaction of monocytes and erythrocytes

Abstract1H spin echo NMR spectroscopy is used to follow the interaction of intact and viable erythrocytes and monocytes obtained from different sources in mixed cultures. After a lag time (270 min) erythrocyte glutathione is observed to become more oxidised. This result is believed to occur as a consequence of monocyte activation generating hydrogen peroxide or hypochlorous acid, which is targeted at the erythrocyte. The red cell in turn employs its sulphydryl system as an anti-oxidant defence

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