Aryl hydroxamic acid analogues as potential therapeutic agents /

A new synthetic pathway to analogues of the aglucones of naturally occurring cyclic hydroxamic acids (2,4-dihydroxy-l,4-benzoxazin-3-ones) has been developed. The new pathway involves the coupling of substituted nitrophenols wdth /-propyl-abromo- O-methoxymethylglycolate. These materials were reductively cyclised to reveal the hydroxamic acid functionality. Removal of the C-2 0-methoxymethyl protecting group was achieved chemoselectively using boron trichloride. The analogue 7-methoxy-2,4-dihydroxy-l,4-benzoxazin-3-one (DIMBOA) was assayed with papain and a semilog plot of activity of papain in the presence of excess DIMBOA was found to be linear. A single exponential equation was suggested as the model for kinetic analysis. '^ Nuclear magnetic resonance (NMR) spectra of a couple of hydroxamates were acquired as reference standards for future mechanistic studies of these compounds as thiol protease inhibitors. A 10% '^-labeled sample ofDIMBOA was also prepared for future mechanistic studies using NMR techniques.

Abrasion, transport and distribution of sediment in selected streams of Southern Ontario and Western New York /

The rate of decrease in mean sediment size and weight per square metre along a 54 km reach of the Credit River was found to depend on variations in the channel geometry. The distribution of a specific sediment size consist of: (1) a transport zone; (2) an accumulation zone; and (3) a depletion zone. These zones shift downstream in response to downcurrent decreases in stream competence. Along a .285 km man-made pond, within the Credit River study area, the sediment is also characterized by downstream shifting accumulation zones for each finer clast size. The discharge required to initiate movement of 8 cm and 6 cm blocks in Cazenovia Creek is closely approximated by Baker and Ritter's equation. Incipient motion of blocks in Twenty Mile Creek is best predicted by Yalin's relation which is more efficient in deeper flows. The transport distance of blocks in both streams depends on channel roughness and geometry. Natural abrasion and distribution of clasts may depend on the size of the surrounding sediment and variations in flow competence. The cumulative percent weight loss with distance of laboratory abraded dolostone is defined by a power function. The decrease in weight of dolostone follows a negative exponential. In the abrasion mill, chipping causes the high initial weight loss of dolostone; crushing and grinding produce most of the subsequent weight loss. Clast size was found to have little effect on the abrasion of dolostone within the diameter range considered. Increasing the speed of the mill increased the initial amount of weight loss but decreased the rate of abrasion. The abrasion mill was found to produce more weight loss than stream action. The maximum percent weight loss determined from laboratory and field abrasion data is approximately 40 percent of the weight loss observed along the Credit River. Selective sorting of sediment explains the remaining percentage, not accounted for by abrasion.

The effects of moisture, cation concentration, temperature, density and composition of soils on their electrical resistivity

The effects. of moisture, cation concentration, dens ity , temper~ t ure and grai n si ze on the electrical resistivity of so il s are examined using laboratory prepared soils. An i nexpen si ve method for preparing soils of different compositions was developed by mixing various size fractions i n the laboratory. Moisture and cation c oncentration are related to soil resistivity by powe r functions, whereas soil resistiv ity and temperature, density, Yo gravel, sand , sil t, and clay are related by exponential functions . A total of 1066 cases (8528 data) from all the experiments were used in a step-wise multiple linear r egression to determine the effect of each variable on soil resistivity. Six variables out of the eight variables studied account for 92.57/. of the total variance in so il resistivity with a correlation coefficient of 0.96. The other two variables (silt and gravel) did not increase the · variance. Moisture content was found to be - the most important Yo clay. variable- affecting s oil res istivi ty followed by These two variables account for 90.81Yo of the total variance in soil resistivity with a correlation ~oefficient ·.of 0 . 95. Based on these results an equation to ' ~~ed{ ct soil r esist ivi ty using moisture and Yo clay is developed . To t est the predicted equation, resistivity measurements were made on natural soils both in s i tu a nd i n the laboratory. The data show that field and laboratory measurements are comparable. The predicted regression line c losely coinciqes with resistivity data from area A and area B soils ~clayey and silty~clayey sands). Resistivity data and the predicted regression line in the case of c layey soils (clays> 40%) do not coincide, especially a t l ess than 15% moisture. The regression equation overestimates the resistivity of so i l s from area C and underestimates for area D soils. Laboratory prepared high clay soils give similar trends. The deviations are probably caused by heterogeneous distribution of mo i sture and difference in the type o f cl ays present in these soils.

Subjective, behavioural and electrophysiological measurements of the time-course and intensity of sleep inertia after a full night of sleep /

Several recent studies have described the period of impaired alertness and performance known as sleep inertia that occurs upon awakening from a full night of sleep. They report that sleep inertia dissipates in a saturating exponential manner, the exact time course being task dependent, but generally persisting for one to two hours. A number of factors, including sleep architecture, sleep depth and circadian variables are also thought to affect the duration and intensity. The present study sought to replicate their findings for subjective alertness and reaction time and also to examine electrophysiological changes through the use of event-related potentials (ERPs). Secondly, several sleep parameters were examined for potential effects on the initial intensity of sleep inertia. Ten participants spent two consecutive nights and subsequent mornings in the sleep lab. Sleep architecture was recorded for a fiiU nocturnal episode of sleep based on participants' habitual sleep patterns. Subjective alertness and performance was measured for a 90-minute period after awakening. Alertness was measured every five minutes using the Stanford Sleepiness Scale (SSS) and a visual analogue scale (VAS) of sleepiness. An auditory tone also served as the target stimulus for an oddball task designed to examine the NlOO and P300 components ofthe ERP waveform. The five-minute oddball task was presented at 15-minute intervals over the initial 90-minutes after awakening to obtain six measures of average RT and amplitude and latency for NlOO and P300. Standard polysomnographic recording were used to obtain digital EEG and describe the night of sleep. Power spectral analyses (FFT) were used to calculate slow wave activity (SWA) as a measure of sleep depth for the whole night, 90-minutes before awakening and five minutes before awakening.

An anharmonic contribution to the Helmholtz free energy O(lambda 6)

The anharmonic contributions of order A6 to the Helmholtz free energy for a crystal in which every atom is on a site of inversion symmetry, have been evaluated The cor~esponding diagrams in the various orders of the perturbation theory have been presented The validity of the expressions given is for high temperatures. Numerical calculations for the diagrams which contribute to the free energy have been worked out for a nearest-n~ighbour central-force model of a facecentered cubic lattice in the high-temperature limit and in the leading term and the Ludwig approximations. The accuracy of the Ludwig approximation in evaluating the Brillouin-zone sums has been investigated. Expansion for all diagrams in the high-temperature limit has been carried out The contribution to the specific heat involves a linear as well as cubic term~ We have applied Lennard-Jones, Morse and Exponential 6 types of potentials. A comparison between the contribution to the free energy of order A6 to that of order A4 has been made.

A29 NMR spin-lattice relaxation study of paramagnetics -doped orthosilictes

A ~si MAS NMR study of spin-lattice relaxation behaviour in paramagnetic-doped crystalline silicates was undertaken, using synthetic magnesium orthosilicate (forsterite) and synthetic zinc orthosilicate (willemite) doped with 0.1% to 20% of Co(II), Ni(II), or CU(II), as experimental systems. All of the samples studied exhibited a longitudinal magnetization return to the Boltzmann distribution of nuclear spin states which followed a stretched-exponential function of time: Y=exp [- (tjTn) n], O

Developing a numerical inverse-theory-based extraction of orientation-dependent relaxation rates from partially- relaxed spectra

Second-rank tensor interactions, such as quadrupolar interactions between the spin- 1 deuterium nuclei and the electric field gradients created by chemical bonds, are affected by rapid random molecular motions that modulate the orientation of the molecule with respect to the external magnetic field. In biological and model membrane systems, where a distribution of dynamically averaged anisotropies (quadrupolar splittings, chemical shift anisotropies, etc.) is present and where, in addition, various parts of the sample may undergo a partial magnetic alignment, the numerical analysis of the resulting Nuclear Magnetic Resonance (NMR) spectra is a mathematically ill-posed problem. However, numerical methods (de-Pakeing, Tikhonov regularization) exist that allow for a simultaneous determination of both the anisotropy and orientational distributions. An additional complication arises when relaxation is taken into account. This work presents a method of obtaining the orientation dependence of the relaxation rates that can be used for the analysis of the molecular motions on a broad range of time scales. An arbitrary set of exponential decay rates is described by a three-term truncated Legendre polynomial expansion in the orientation dependence, as appropriate for a second-rank tensor interaction, and a linear approximation to the individual decay rates is made. Thus a severe numerical instability caused by the presence of noise in the experimental data is avoided. At the same time, enough flexibility in the inversion algorithm is retained to achieve a meaningful mapping from raw experimental data to a set of intermediate, model-free

Bio-inspired optimization & sampling technique for side-chain packing in MCCE

The prediction of proteins' conformation helps to understand their exhibited functions, allows for modeling and allows for the possible synthesis of the studied protein. Our research is focused on a sub-problem of protein folding known as side-chain packing. Its computational complexity has been proven to be NP-Hard. The motivation behind our study is to offer the scientific community a means to obtain faster conformation approximations for small to large proteins over currently available methods. As the size of proteins increases, current techniques become unusable due to the exponential nature of the problem. We investigated the capabilities of a hybrid genetic algorithm / simulated annealing technique to predict the low-energy conformational states of various sized proteins and to generate statistical distributions of the studied proteins' molecular ensemble for pKa predictions. Our algorithm produced errors to experimental results within .acceptable margins and offered considerable speed up depending on the protein and on the rotameric states' resolution used.

Phonon spectra and temperature variation of thermodynamic properties of fcc metals via Finnis-Sinclair type many body potentials: Sutton-Chen and improved Sutton-Chen models

Volume(density)-independent pair-potentials cannot describe metallic cohesion adequately as the presence of the free electron gas renders the total energy strongly dependent on the electron density. The embedded atom method (EAM) addresses this issue by replacing part of the total energy with an explicitly density-dependent term called the embedding function. Finnis and Sinclair proposed a model where the embedding function is taken to be proportional to the square root of the electron density. Models of this type are known as Finnis-Sinclair many body potentials. In this work we study a particular parametrization of the Finnis-Sinclair type potential, called the "Sutton-Chen" model, and a later version, called the "Quantum Sutton-Chen" model, to study the phonon spectra and the temperature variation thermodynamic properties of fcc metals. Both models give poor results for thermal expansion, which can be traced to rapid softening of transverse phonon frequencies with increasing lattice parameter. We identify the power law decay of the electron density with distance assumed by the model as the main cause of this behaviour and show that an exponentially decaying form of charge density improves the results significantly. Results for Sutton-Chen and our improved version of Sutton-Chen models are compared for four fcc metals: Cu, Ag, Au and Pt. The calculated properties are the phonon spectra, thermal expansion coefficient, isobaric heat capacity, adiabatic and isothermal bulk moduli, atomic root-mean-square displacement and Gr\"{u}neisen parameter. For the sake of comparison we have also considered two other models where the distance-dependence of the charge density is an exponential multiplied by polynomials. None of these models exhibits the instability against thermal expansion (premature melting) as shown by the Sutton-Chen model. We also present results obtained via pure pair potential models, in order to identify advantages and disadvantages of methods used to obtain the parameters of these potentials.

Ligand Design for Dual Property Single Molecule Magnets

This thesis describes two different approaches for the preparation of polynuclear clusters with interesting structural, magnetic and optical properties. Firstly, exploiting p-tert-butylcalix[4]arene (TBC4) macrocycles together with selected Ln(III) ions for the assembly of emissive single molecule magnets, and secondly the preparation and coordination of a chiral mpmH ligand with selected 3d transition metal ions, working towards the discovery of chiral polynuclear clusters. In Project 1, the coordination chemistry of the TBC4 macrocycle together with Dy(III) and Tb(III) afforded two Ln6[TBC4]2 complexes that have been structurally, magnetically and optically characterized. X-ray diffraction studies reveal that both complexes contain an octahedral core of Ln6 ions capped by two fully deprotonated TBC4 macrocycles. Although the unit cells of the two complexes are very similar, the coordination geometries of their Ln(III) ions are subtly different. Variable temperature ac magnetic susceptibility studies reveal that both complexes display single molecule magnet (SMM) behaviour in zero dc field and the energy barriers and associated pre-exponential factors for each relaxation process have been determined. Low temperature solid state photoluminescence studies reveal that both complexes are emissive; however, the f-f transitions within the Dy6 complex were masked by broad emissions from the TBC4 ligand. In contrast, the Tb(III) complex displayed green emission with the spectrum comprising four sharp bands corresponding to 5D4 → 7FJ transitions (where J = 3, 4, 5 and 6), highlighting that energy transfer from the TBC4 macrocycle to the Tb(III) ion is more effective than to Dy. Examples of zero field Tb(III) SMMs are scarce in the chemical literature and the Tb6[TBC4]2 complex represents the first example of a Tb(III) dual property SMM assembled from a p-tert-butylcalix[4]arene macrocycle with two magnetically derived energy barriers, Ueff of 79 and 63 K. In Project 2, the coordination of both enantiomers of the chiral ligand, α-methyl-2-pyridinemethanol (mpmH) to Ni(II) and Co(II) afforded three polynuclear clusters that have been structurally and magnetically characterized. The first complex, a Ni4 cluster of stoichiometry [Ni4(O2CCMe3)4(mpm)4]·H2O crystallizes in a distorted cubane topology that is well known in Ni(II) cluster chemistry. The final two Co(II) complexes crystallize as a linear mixed valence trimer with stoichiometry [Co3(mpm)6]·(ClO4)2, and a Co4 mixed valence complex [Co(II)¬2Co(III)2(NO3)2(μ-mpm)4(ONO2)2], whose structural topology resembles that of a defective double cubane. All three complexes crystallize in chiral space groups and circular dichroism experiments further confirm that the chirality of the ligand has been transferred to the respective coordination complex. Magnetic susceptibility studies reveal that for all three complexes, there are competing ferro- and antiferromagnetic exchange interactions. The [Co(II)¬2Co(III)2(NO3)2(μ-mpm)4(ONO2)2] complex represents the first example of a chiral mixed valence Co4 cluster with a defective double cubane topology.