The synthesis and evaluation of small organic molecules as cholecystokinin antagonists

Cholecystokinin (CCK) is a peptide hormone, present in the alimentary and the CNS. It is the most abundant peptide in the brain. CCK has been implicated in a number of disorders. The link between CCK and anxiety was the basis for this research. A comprehensive discussion on the many types of CCK receptor antagonists is included. For the drug discovery process, a number of synthetic approaches have been investigated and alternative chemical approaches developed. 1,4-Benzodiazepine analogues were prepared, with substitutents In the 1,2 & 3- position of the benzodiazepine scaffold varied, and substituted 3-anilino benzodiazepines exhibited the greatest in vitro activity towards the CCKA receptor subtype. Through extensive screening, pyrazolinone-ureido derivatives were identified, optimised, SAR studied and re-screened. A comprehensive in vivo study on the most active analogue is included, which has a number of common structural features with L-36S, 260 including activity. Pyrazolinone-amide derivatives, bearing the tryptophan moiety were equally active. A number of existing and novel furan- 2(SH)-one building blocks were prepared, from which a selected mini-library of 4- amino-substituted furan-2(SH)-ones were prepared and evaluated. All synthesised compounds were evaluated in a CCK radiolabelled binding assay (CCKA & CCKB), with compounds demonstrating receptor selectivity and lead structures being discovered. The work in this thesis has identified a number of highly active prime structures, from which further investigations are essential in providing more in vitro & in vivo data and the need to prepare more analogues.

A sensing mechanism for the detection of carbon nanotubes using selective photoluminescent probes based on ionic complexes with organic dyes

The multifunctional properties of carbon nanotubes (CNTs) make them a powerful platform for unprecedented innovations in a variety of practical applications. As a result of the surging growth of nanotechnology, nanotubes present a potential problem as an environmental pollutant, and as such, an efficient method for their rapid detection must be established. Here, we propose a novel type of ionic sensor complex for detecting CNTs – an organic dye that responds sensitively and selectively to CNTs with a photoluminescent signal. The complexes are formed through Coulomb attractions between dye molecules with uncompensated charges and CNTs covered with an ionic surfactant in water. We demonstrate that the photoluminescent excitation of the dye can be transferred to the nanotubes, resulting in selective and strong amplification (up to a factor of 6) of the light emission from the excitonic levels of CNTs in the near-infrared spectral range, as experimentally observed via excitation-emission photoluminescence (PL) mapping. The chirality of the nanotubes and the type of ionic surfactant used to disperse the nanotubes both strongly affect the amplification; thus, the complexation provides sensing selectivity towards specific CNTs. Additionally, neither similar uncharged dyes nor CNTs covered with neutral surfactant form such complexes. As model organic molecules, we use a family of polymethine dyes with an easily tailorable molecular structure and, consequently, tunable absorbance and PL characteristics. This provides us with a versatile tool for the controllable photonic and electronic engineering of an efficient probe for CNT detection.

The structure and dynamics of 2-dimensional fluids in swelling clays

The interlayer pores of swelling 2:1 clays provide an ideal 2-dimensional environment in which to study confined fluids. In this paper we discuss our understanding of the structure and dynamics of interlayer fluid species in expanded clays, based primarily on the outcome of recent molecular modelling and neutron scattering studies. Counterion solvation is compared with that measured in bulk solutions, and at a local level the cation-oxygen coordination is found to be remarkably similar in these two environments. However, for the monovalent ions the contribution to the first coordination shell from the clay surfaces increases with counterion radius. This gives rise to inner-sphere (surface) complexes in the case of potassium and caesium. In this context, the location of the negative clay surface charge (i.e. arising from octahedral or tetrahedral substitution) is also found to be of major importance. Divalent cations, such as calcium, eagerly solvate to form outer-sphere complexes. These complexes are able to pin adjacent clay layers together, and thereby prevent colloidal swelling. Confined water molecules form hydrogen bonds to each other and to the clays' surfaces. In this way their local environment relaxes to close to the bulk water structure within two molecular layers of the clay surface. Finally, we discuss the way in which the simple organic molecules methane, methanol and ethylene glycol behave in the interlayer region of hydrated clays. Quasi-elastic neutron scattering of isotopically labelled interlayer CH 3OD and (CH2OD)2 in deuterated clay allows us to measure the diffusion of the CH3- and CH2-groups in both clay and liquid environments. We find that in both the one-layer methanol solvates and the two-layer glycol solvates the diffusion of the most mobile organic molecules is close to that in the bulk solution.

Role of GSH in estrone sulfate binding and translocation by the multidrug resistance protein 1 (MRP1/ABCC1)

Multidrug resistance protein 1 (MRP1/ABCC1) is an ATP-dependent efflux pump that can confer resistance to multiple anticancer drugs and transport conjugated organic anions. Unusually, transport of several MRP1 substrates requires glutathione (GSH). For example, estrone sulfate transport by MRP1 is stimulated by GSH, vincristine is co-transported with GSH, or GSH can be transported alone. In the present study, radioligand binding assays were developed to investigate the mechanistic details of GSH-stimulated transport of estrone sulfate by MRP1. We have established that estrone sulfate binding to MRP1 requires GSH, or its non-reducing analogue S-methyl GSH (S-mGSH), and further that the affinity (Kd) of MRP1 for estrone sulfate is 2.5-fold higher in the presence of S-mGSH than GSH itself. Association kinetics show that GSH binds to MRP1 first, and we propose that GSH binding induces a conformational change, which makes the estrone sulfate binding site accessible. Binding of non-hydrolyzable ATP analogues to MRP1 decreases the affinity for estrone sulfate. However, GSH (or S-mGSH) is still required for estrone sulfate binding, and the affinity for GSH is unchanged. Estrone sulfate affinity remains low following hydrolysis of ATP. The affinity for GSH also appears to decrease in the post-hydrolytic state. Our results indicate ATP binding is sufficient for reconfiguration of the estrone sulfate binding site to lower affinity and argue for the presence of a modulatory GSH binding site not associated with transport of this tripeptide. A model for the mechanism of GSH-stimulated estrone sulfate transport is proposed.

Catalysing sustainable fuel and chemical synthesis

Concerns over the economics of proven fossil fuel reserves, in concert with government and public acceptance of the anthropogenic origin of rising CO2 emissions and associated climate change from such combustible carbon, are driving academic and commercial research into new sustainable routes to fuel and chemicals. The quest for such sustainable resources to meet the demands of a rapidly rising global population represents one of this century’s grand challenges. Here, we discuss catalytic solutions to the clean synthesis of biodiesel, the most readily implemented and low cost, alternative source of transportation fuels, and oxygenated organic molecules for the manufacture of fine and speciality chemicals to meet future societal demands.

Bio-based chemicals from biorefining:carbohydrate conversion and utilisation

The quest for sustainable sources of fuels and chemicals to meet the demands of a rapidly rising global population represents one of this century's grand challenges. Biomass offers the most readily implemented, and low cost, solution for transportation fuels, and the only non-petroleum route to organic molecules for the manufacture of bulk, fine and speciality chemicals and polymers. Chemical processing of such biomass-derived building blocks requires catalysts compatible with hydrophilic, bulky substrates to facilitate the selective deoxygenation of highly functional bio-molecules to their target products. This chapter addresses the challenges associated with carbohydrate utilisation as a sustainable feedstock, highlighting innovations in catalyst and process design that are needed to deliver high-value chemicals from biomass-derived building blocks. © 2014 Woodhead Publishing Limited. All rights reserved.

Catalyst design for biorefining

The quest for sustainable resources to meet the demands of a rapidly rising global population while mitigating the risks of rising CO2 emissions and associated climate change, represents a grand challenge for humanity. Biomass offers the most readily implemented and low-cost solution for sustainable transportation fuels, and the only non-petroleum route to organic molecules for the manufacture of bulk, fine and speciality chemicals and polymers. To be considered truly sustainable, biomass must be derived fromresources which do not compete with agricultural land use for food production, or compromise the environment (e.g. via deforestation). Potential feedstocks include waste lignocellulosic or oil-based materials derived from plant or aquatic sources, with the so-called biorefinery concept offering the co-production of biofuels, platform chemicals and energy; analogous to today's petroleum refineries which deliver both high-volume/low-value (e.g. fuels and commodity chemicals) and lowvolume/ high-value (e.g. fine/speciality chemicals) products, thereby maximizing biomass valorization. This article addresses the challenges to catalytic biomass processing and highlights recent successes in the rational design of heterogeneous catalysts facilitated by advances in nanotechnology and the synthesis of templated porous materials, as well as the use of tailored catalyst surfaces to generate bifunctional solid acid/base materials or tune hydrophobicity.

Emergence of additional visible range photoluminescence due to aggregation of cyanine dye:astraphloxin on carbon nanotubes dispersed with anionic surfactant

Self-organization of organic molecules with carbon nanomaterials leads to formation of functionalized molecular nano-complexes with advanced features. We present a study of physical and chemical properties of carbon nanotube-surfactant-indocarbocyanine dye (astraphloxin) in water focusing on aggregation of the dye and resonant energy transfer from the dye to the nanotubes. Self-assembly of astraphloxin is evidenced in absorbance and photoluminescence depending dramatically on the concentrations of both the dye and surfactant in the mixtures. We observed an appearance of new photoluminescence peaks in visible range from the dye aggregates. The aggregates characterized with red shifted photoluminescence peaks at 595, 635 and 675 nm are formed mainly due to the presence of surfactant at the premicellar concentration. The energy transfer from the dye to the nanotubes amplifying near-infrared photoluminescence from the nanotubes is not affected by the aggregation of astraphloxin molecules providing important knowledge for further development of advanced molecular nano-complexes. The aggregation with the turned-on peaks and the energy transfer with amplified photoluminescence create powerful tools of visualization and/or detection of the nanotubes in visible and near-infrared spectral range, respectively, boosting its possible applications in sensors, energy generation/storage, and healthcare.

Organotellurium compounds for metal organic vapour phase epitaxy

The infra-red detector material cadmium mercury telluride can be grown by the technique of Metal Organic Vapour Phase Epitaxy using simple alkyl telluride compounds as the source of tellurium. New tellurium precursors are required in order to overcome handling and toxicity problems and to reduce the growth temperature in preparing the material. A range of diaryltellurium(IV) dicarboxylates and some 2-(2'-pyridyl)phenyl-tellurium(II) and tellurium(IV) monocarboxylates have been synthesised and characterised by infra-red, 13C N.M.R. and mass spectroscopy. Infra-red spectroscopy has been used to determine the mode of bonding of the carboxylate ligand to tellurium. Synthetic methods have been devised for the preparation of diorganotritellurides (R2Te3) and mixed diorganotetrachalcogenides (RTeSeSeTeR). A mechanism for the formation of the tritellurides based on aerobic conditions is proposed. The reaction of ArTe- with (ClCH2CH2)3N leads to tripod-like multidentate ligands (ArTeCH2CH2)3N which form complexes with the ions Hg(II), Cd(II), Cu(I), Pt(II) and Pd(II). Synthetic routes to aryltelluroalkylamines and arylselenoalkylamines are also reported. The crystal structure of 2-(2'-pyridyl)phenyltellurium(II) bromide has been solved in which there are six molecules present within the unit cell. There are no close intermolecular Te---Te interactions and the molecules are stabilised by short Te---N intramolecular contacts. The crystal structure of 2-(2'-pyridyl)phenylselenium(II)-tribromomercurate(II) is also presented. A study of the Raman vibrational spectra of some tellurated azobenzenes and 2-phenylpyridines shows spectra of remarkably far superior quality to those obtained using infra-red spectroscopy.

Molecular mechanisms of salt effects on carbon nanotube dispersions in an organic solvent (N-methyl-2-pyrrolidone)

We consider the effects of salt (sodium iodide) on pristine carbon nanotube (CNT) dispersions in an organic solvent, N-methyl-2-pyrrolidone (NMP). We investigate the molecular-scale mechanisms of ion interactions with the nanotube surface and we show how the microscopic ion-surface interactions affect the stability of CNT dispersions in NMP. In our study we use a combination of fully atomistic Molecular Dynamics simulations of sodium and iodide ions at the CNT-NMP interface with direct experiments on the CNT dispersions. In the experiments we analyze the effects of salt on the stability of the dispersions by photoluminescence (PL) and optical absorption spectroscopy of the samples as well as by visual inspection. By fully atomistic Molecular Dynamics simulations we investigate the molecular-scale mechanisms of sodium and iodide ion interactions with the nanotube surface. Our simulations reveal that both ions are depleted from the CNT surface in the CNT-NMP dispersions mainly due to the two reasons: (1) there is a high energy penalty for the ion partial desolvation at the CNT surface; (2) NMP molecules form a dense solvation layer at the CNT surface that prevents ions to come close to the CNT surface. As a result, an increase of the salt concentration increases the "osmotic" stress in the CNT-NMP system and, thus, decreases the stability of the CNT dispersions in NMP. Direct experiments confirm the simulation results: addition of NaI salt into the NMP dispersions of pristine CNTs leads to precipitation of CNTs (bundle formation) even at very small salt concentration (∼10 -3 mol L -1). In line with the simulation predictions, the effect increases with the increase of the salt concentration. Overall, our results show that dissolved salt ions have strong effects on the stability of CNT dispersions. Therefore, it is possible to stimulate the bundle formation in the CNT-NMP dispersions and regulate the overall concentration of nanotubes in the dispersions by changing the NaI concentration in the solvent. © 2012 The Royal Society of Chemistry.