Combinatorial solid phase synthesis of multiply substituted 1,4-benzodiazepines and affinity studies on the CCK2 receptor (Part 1)

One hundred sixty-eight multiply substituted 1,4-benzodiazepines have been prepared by a five-step solid-phase combinatorial approach using syn-phase crowns as a solid support and a hydroxymethyl-phenoxy-acetamido linkage (Wang linker). The substituents of the 1,4-benzodiazepine scaffold have been varied in the -3, -5, -7, and 8-positions and the combinatorial library was evaluated in a cholecystokinin (CCK) radioligand binding assay. 3-Alkylated 1,4-benzodiazepines with selectivity towards the CCK-B (CCK2) receptor have been optimized on the lipophilic side chain, the ketone moiety, and the stereochemistry at the 3-position. Various novel 3-alkylated compounds were synthesized and [S]3-propyl-5-phenyl-1,4-benzodiazepin-2-one, [S]NV-A, has shown a CCK-B selective binding at about 180 nM. Fifty-eight compounds of this combinatorial library were purified by preparative TLC and 25 compounds were isolated and fully characterized by TLC, IR, APCI-MS, and 1H/13C-NMR spectroscopy.

Experimental and theoretical studies on a distributed temperature sensor based on Brillouin scattering

Results are reported from recent research on the use of the Brillouin gain/loss mechanism for distributed sensing. A theoretical model of the interaction of the pulsed and CW beams is described and compared with experiments. Results from a system with a 51 km sensing length are presented. We finally investigate issues related to the variation within the sensing fiber of the polarizations of the two beams.

Functional neuroimaging and behavioural studies on global form processing in the human visual system

Magnetoencephalography (MEG), functional magnetic resonance imaging (fMRI) and behavioural experiments were used to investigate the neural processes underlying global form perception in human vision. Behavioural studies using Glass patterns examined sensitivity for detecting radial, rotational and horizontal structure. Neuroimaging experiments using either Glass patterns or arrays of Gabor patches determined the spatio-temporal neural responseto global form. MEG data were analysed using synthetic aperture magnetometry (SAM) to spatially map event-related cortical oscillatory power changes: the temporal sequencing of activity within a discrete cortical area was determined using a Morlet wavelet transform. A case study was conducted to determine the effects of strbismic amblyopia on global form processing: all other observers were normally-sighted. The main findings from normally-sighted observers were: 1) sensitivity to horizontal structure was less than for radial or rotational structure; 2) the neural response to global structure was a reduction in cortical oscillatory power (10-30 Hz) within a network of extrastriate areas, including V4 and V3a; 3) the extend of reduced cortical power was least for horizontal patters; 4) V1 was not identified as a region of peak activity with either MEG or fMRI. The main findings with the strabismic amblyope were: 1) sensitivity for detection of radial, rotational, and horizontal structure was reduced when viewed with the amblyopic- relative to the fellow- eye; 2) cortical power changes within V4 to the presentation of rotational Glass patterns were less when viewed with the amblyopic- compared with the fellow- eye. The main conclusions are: 1) a network of extrastriate cortical areas are involved in the analysis of global form, with the most prominent change in neural activity being a reduction in oscillatory power within the 10-30 Hz band; 2) in strabismic amblyopia, the neuronal assembly associated with form perception in extrastriate cortex may be dysfunctional, the nature of this dysfunction may be a change in the normal temporal pattern of neuronal discharges; 3) MEG, fMRI and behavioural measures support the notion that different neural processes underlie the perception of horizontal as opposed to radial or rotational structure.

Histochemical and ultrastructural studies on the islets of langerhans of lean and obese hyperglycaemic mice with age

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Experimental and theoretical studies on six-membered ring hydrogen bond systems in crystalline drug substances

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Experimental and theoretical studies on molecular geometry and polymorphism in crystalline drug substances

DUE TO COPYRIGHT RESTRICTIONS ONLY AVAILABLE FOR CONSULTATION AT ASTON UNIVERSITY LIBRARY AND INFORMATION SERVICES WITH PRIOR ARRANGEMENT

Experimental and theoretical studies on a distributed temperature sensor based on Brillouin scattering

Results are reported from recent research on the use of the Brillouin gain/loss mechanism for distributed sensing. A theoretical model of the interaction of the pulsed and CW beams is described and compared with experiments. Results from a system with a 51 km sensing length are presented. We finally investigate issues related to the variation within the sensing fiber of the polarizations of the two beams.

Experimental and theoretical studies on a distributed temperature sensor based on Brillouin scattering

Results are reported from recent research on the use of the Brillouin gain/loss mechanism for distributed sensing. A theoretical model of the interaction of the pulsed and CW beams is described and compared with experiments. Results from a system with a 51 km sensing length are presented. We finally investigate issues related to the variation within the sensing fiber of the polarizations of the two beams.

Electrical and optical studies on carbon nanotube arrays

Single-walled carbon nanotubes (SWNTs) have been studied as a prominent class of high performance electronic materials for next generation electronics. Their geometry dependent electronic structure, ballistic transport and low power dissipation due to quasi one dimensional transport, and their capability of carrying high current densities are some of the main reasons for the optimistic expectations on SWNTs. However, device applications of individual SWNTs have been hindered by uncontrolled variations in characteristics and lack of scalable methods to integrate SWNTs into electronic devices. One relatively new direction in SWNT electronics, which avoids these issues, is using arrays of SWNTs, where the ensemble average may provide uniformity from device to device, and this new breed of electronic material can be integrated into electronic devices in a scalable fashion. This dissertation describes (1) methods for characterization of SWNT arrays, (2) how the electrical transport in these two-dimensional arrays depend on length scales and spatial anisotropy, (3) the interaction of aligned SWNTs with the underlying substrate, and (4) methods for scalable integration of SWNT arrays into electronic devices. The electrical characterization of SWNT arrays have been realized by polymer electrolyte-gated SWNT thin film transistors (TFTs). Polymer electrolyte-gating addresses many technical difficulties inherent to electrical characterization by gating through oxide-dielectrics. Having shown polymer electrolyte-gating can be successfully applied on SWNT arrays, we have studied the length scaling dependence of electrical transport in SWNT arrays. Ultrathin films formed by sub-monolayer surface coverage of SWNT arrays are very interesting systems in terms of the physics of two-dimensional electronic transport. We have observed that they behave qualitatively different than the classical conducting films, which obey the Ohm’s law. The resistance of an ultrathin film of SWNT arrays is indeed non-linear with the length of the film, across which the transport occurs. More interestingly, a transition between conducting and insulating states is observed at a critical surface coverage, which is called percolation limit. The surface coverage of conducting SWNTs can be manipulated by turning on and off the semiconductors in the SWNT array, leading to the operation principle of SWNT TFTs. The percolation limit depends also on the length and the spatial orientation of SWNTs. We have also observed that the percolation limit increases abruptly for aligned arrays of SWNTs, which are grown on single crystal quartz substrates. In this dissertation, we also compare our experimental results with a two-dimensional stick network model, which gives a good qualitative picture of the electrical transport in SWNT arrays in terms of surface coverage, length scaling, and spatial orientation, and briefly discuss the validity of this model. However, the electronic properties of SWNT arrays are not only determined by geometrical arguments. The contact resistances at the nanotube-nanotube and nanotube-electrode (bulk metal) interfaces, and interactions with the local chemical groups and the underlying substrates are among other issues related to the electronic transport in SWNT arrays. Different aspects of these factors have been studied in detail by many groups. In fact, I have also included a brief discussion about electron injection onto semiconducting SWNTs by polymer dopants. On the other hand, we have compared the substrate-SWNT interactions for isotropic (in two dimensions) arrays of SWNTs grown on Si/SiO2 substrates and horizontally (on substrate) aligned arrays of SWNTs grown on single crystal quartz substrates. The anisotropic interactions associated with the quartz lattice between quartz and SWNTs that allow near perfect horizontal alignment on substrate along a particular crystallographic direction is examined by Raman spectroscopy, and shown to lead to uniaxial compressive strain in as-grown SWNTs on single crystal quartz. This is the first experimental demonstration of the hard-to-achieve uniaxial compression of SWNTs. Temperature dependence of Raman G-band spectra along the length of individual nanotubes reveals that the compressive strain is non-uniform and can be larger than 1% locally at room temperature. Effects of device fabrication steps on the non-uniform strain are also examined and implications on electrical performance are discussed. Based on our findings, there are discussions about device performances and designs included in this dissertation. The channel length dependences of device mobilities and on/off ratios are included for SWNT TFTs. Time response of polymer-electrolyte gated SWNT TFTs has been measured to be ~300 Hz, and a proof-of-concept logic inverter has been fabricated by using polymer electrolyte gated SWNT TFTs for macroelectronic applications. Finally, I dedicated a chapter on scalable device designs based on aligned arrays of SWNTs, including a design for SWNT memory devices.

Patterns of sedentary behavior : insights from observational and experimental studies on body composition and energy expenditure

It is recognized that sedentary behavior (SB) has deleterious effects on numerous health outcomes and it appears that physiological mechanisms underlying these harms are distinct from the ones explaining moderate-to-vigorous physical activity (MVPA) benefits. Sedentary behavior represents a large portion of human’s life and is increasing with technological development. A new current of opinion supports the idea that the manner SB is accumulated plays an important role. This dissertation presents six research studies conducted under the scope of SB. In the methodological area, the first study highlighted the magnitude of potential errors in estimating SB and its patterns from common alternative methods (accelerometer and heart rate monitor) compared to ActivPAL. This study presented the accelerometer as a valid method at a group level. Two studies (2 and 5) were performed in older adults (the most sedentary group in the population) to test the associations for SB patterns with abdominal obesity using accelerometry. The findings showed positive graded associations for prolonged sedentary bouts with abdominal obesity and showed that those who interrupted SB more frequently were less likely to present abdominal obesity. Therefore, public health recommendations regarding breaking up SB more often are expected to be relevant. The associations between sedentary patterns and abdominal obesity were independent of MVPA in older adults. However, the low MVPA in this group makes it unclear whether this independent relationship still exists if highly active persons are analysed. Study 3 inovates by examining the association of SB with body fatness in highly trained athletes and found SB to predict total fat mass and trunk fat mass, independently of age and weekly training time. Study 4 also brings novelty to this research field by quantifying the metabolic and energetic cost of the transition from sitting to standing and then sitting back down (a break), informing about the modest energetic costs (0.32 kcal·min−1). Finally, from a successful multicomponent pilot intervention to reduce and break up SB (study 6), an important behavioral resistance to make more sit/stand transitions despite successfully reducing sitting time (~ 1.85 hours·day-1) was found, which may be relevant to inform future behavioral modification programs. The present work provides observational and experimental evidence on the relation for SB patterns with body composition outcomes and energy regulation that may be relevant for public health interventions.

Kinetic and mechanistic studies on unconventional antioxidant activities of natural compounds

In chapter one, the autoxidation kinetics of natural oil substrates, including, triglyceric sunflower oil, olive oil, terpenic squalene, and p-cymene were calibrated through differential oximetry methods. Calibration allows their use as reference oxidizable substrates for further studies, e.g. for quantitative testing of antioxidants under biomimetic settings. Several essential oils samples, of different botanical species or different productions of same species were studied for their antioxidant activity in inhibited autoxidation kinetics. Their antioxidant activities were matched with their composition analyzed by GC-MS. In chapter two, the molecular mechanism of the synergy between the common phenolic antioxidants such as tocopherol and catechols with widespread essential component gamma-terpinene was studied through lipid oxidation kinetics. Wherein, gamma-terpinene was able to disclose the key intermediacy HOO·, which acted as a reducing agent regenerating the phenolic antioxidant. This counterintuitive role of HOO· radicals was further investigated in detail and allowed to rationalize for the first time the purported antioxidant behavior of PDA melanin nanoparticles. It will also open to a deeper understanding of the redox biology of quinones. Regarding melanin, its role is broadly important in living organisms and its control, including its inhibition, is of great importance with several relevant applications ranging from food preservation to control of human skin pigmentation. In chapter three, an oximetry method combined with the traditional UV-Vis spectroscopy was developed to study the tyrosinase inhibition kinetics, which allowed identifying Glabridin (from G. glabra, L.), as one of the most effective natural tyrosinase inhibitors.

Kinetic and mechanistic studies on peroxidation and stabilization of lipids with industrial and biological relevance

Lipid peroxidation is a complex mechanism that causes the degradation of lipid material of both industrial and biological significance. During processing, it is known that thermal stress produces oxidation and polymerization of oils. Additionally, biological lipids with both structural and bioactive roles are prone to peroxidation, which can have pathogenic effects including cancer and long-term degenerative disorders. To create innovative strategies to slow down the deterioration of lipids, it is crucial to improve our understanding of oxidation reactions and kinetics. To this purpose, Chapter II of this thesis focuses on the kinetic study of the oxidation reactions that take place during the thermal processing of bio-oils for industrial application. Through a new method it was possible to evaluate the kinetic parameters of oxidation of various lipid materials. This allowed us to distinguish between the different lipid materials based on their intrinsic properties. The effect of 18 antioxidants from the major families of natural and synthetic phenols were studied using the same methodology in order to acquire crucial data for enhancing the antioxidant activity of phenols based on structure-activity at high temperatures. Finally, it has been described how the antioxidant activity of α-tocopherol, revealed to be scarce in our conditions, can be improved in the presence of gamma-terpinene, through a synergistic action. Chapter III describes the synthesis and study of the antioxidant activity of polydopamine nanoparticles, in order to clarify the unclear mechanism of action of this material. Finally, in Chapter IV it was reported how the gamma-terpinene strongly inhibits the peroxidation of unsaturated lipids in heterogeneous model systems (micelles and liposomes) by forming hydroperoxyl radicals which diffuse outside the lipid nucleus, blocking the propagation of the chain radical. Furthermore, gamma-terpinene shows a very potent protective activity against ferroptosis being effective in the nanomolar range in the human neuroblastoma cell model.