Synthesis and structure-activity relationship studies of CD4 down-modulating cyclotriazadisulfonamide (CADA) analogues

HIV attachment via the CD4 receptor is an important target for developing novel approaches to HIV chemotherapy. Cyclotriazadisulfonamide (CADA) inhibits HIV at submicromolar levels by specifically down-modulating cell-surface and intracellular CD4. An effective five-step synthesis of CADA in 30% overall yield is reported. This synthesis has also been modified to produce more than 50 analogues. Many tail-group analogues have been made by removing the benzyl tail of CADA and replacing it with various alkyl, acyl, alkoxycarbonyl and aminocarbonyl substituents. A series of sidearm analogues, including two unsymmetrical compounds, have also been prepared by modifying the CADA synthesis, replacing the toluenesulfonyl sidearms with other sulfonyl groups. Testing 30 of these compounds in MT-4 cells shows a wide range of CD4 down-modulation potency, which correlates with ability to inhibit HIV-1. Three-dimensional quantitative structure-activity relationship (3D-QSAR) models were constructed using comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) approaches. The X-ray crystal structures of four compounds, including CADA, show the same major conformation of the central 12-membered ring. The solid-state structure of CADA was energy minimized and used to generate the remaining 29 structures, which were similarly minimized and aligned to produce the 3D-QSAR models. Both models indicate that steric bulk of the tail group, and, to a lesser extent, the sidearms mainly determine CD4 down-modulation potency in this series of compounds.

Algorithmic statistical analysis of electrophysiological data for the investigation of structure-activity relationship in single neurons

We are developing computational tools supporting the detailed analysis of the dependence of neural electrophysiological response on dendritic morphology. We approach this problem by combining simulations of faithful models of neurons (experimental real life morphological data with known models of channel kinetics) with algorithmic extraction of morphological and physiological parameters and statistical analysis. In this paper, we present the novel method for an automatic recognition of spike trains in voltage traces, which eliminates the need for human intervention. This enables classification of waveforms with consistent criteria across all the analyzed traces and so it amounts to reduction of the noise in the data. This method allows for an automatic extraction of relevant physiological parameters necessary for further statistical analysis. In order to illustrate the usefulness of this procedure to analyze voltage traces, we characterized the influence of the somatic current injection level on several electrophysiological parameters in a set of modeled neurons. This application suggests that such an algorithmic processing of physiological data extracts parameters in a suitable form for further investigation of structure-activity relationship in single neurons.

Quantitative structure of an acetate dye molecule analogue at the TiO2- acetic acid interface

The positions of atoms in and around acetate molecules at the rutile TiO2(110) interface with 0.1 M acetic acid have been determined with a precision of ±0.05 Å. Acetate is used as a surrogate for the carboxylate groups typically employed to anchor monocarboxylate dye molecules to TiO2 in dye-sensitised solar cells (DSSC). Structural analysis reveals small domains of ordered (2 x 1) acetate molecules, with substrate atoms closer to their bulk terminated positions compared to the clean UHV surface. Acetate is found in a bidentate bridge position, binding through both oxygen atoms to two five-fold titanium atoms such that the molecular plane is along the [001] azimuth. Density functional theory calculations provide adsorption geometries in excellent agreement with experiment. The availability of these structural data will improve the accuracy of charge transport models for DSSC.

Possible pre-dissociation of diorganotin dihalide complexes: relationship between antitumour activity and structure

An examination of crystallographic data has indicated that the structure/activity relationship for diorganotin dihalide complexes is different from that of other metal dihalides, in that the SnN bond lengths appear to determine the antitumour activity.

The extrapolation problem and how population modeling can help

We argue that population modeling can add value to ecological risk assessment by reducing uncertainty when extrapolating from ecotoxicological observations to relevant ecological effects. We review other methods of extrapolation, ranging from application factors to species sensitivity distributions to suborganismal (biomarker and "-omics'') responses to quantitative structure activity relationships and model ecosystems, drawing attention to the limitations of each. We suggest a simple classification of population models and critically examine each model in an extrapolation context. We conclude that population models have the potential for adding value to ecological risk assessment by incorporating better understanding of the links between individual responses and population size and structure and by incorporating greater levels of ecological complexity. A number of issues, however, need to be addressed before such models are likely to become more widely used. In a science context, these involve challenges in parameterization, questions about appropriate levels of complexity, issues concerning how specific or general the models need to be, and the extent to which interactions through competition and trophic relationships can be easily incorporated.

QSAR studies of multidentate nitrogen ligands used in lanthanide and actinide extraction processes

Quantitative structure activity relationships (QSARs) have been developed to optimise the choice of nitrogen heterocyclic molecules that can be used to separate the minor actinides such as americium(III) from europium(III) in the aqueous PUREX raffinate of nuclear waste. Experimental data on distribution coefficients and separation factors (SFs) for 47 such ligands have been obtained and show SF values ranging from 0.61 to 100. The ligands were divided into a training set of 36 molecules to develop the QSAR and a test set of 11 molecules to validate the QSAR. Over 1500 molecular descriptors were calculated for each heterocycle and the Genetic Algorithm was used to select the most appropriate for use in multiple regression equations. Equations were developed fitting the separation factors to 6-8 molecular descriptors which gave r(2) values of >0.8 for the training set and values of >0.7 for the test set, thus showing good predictive quality. The descriptors used in the equations were primarily electronic and steric. These equations can be used to predict the separation factors of nitrogen heterocycles not yet synthesised and/or tested and hence obtain the most efficient ligands for lanthanide and actinide separation. (C) 2003 Elsevier B.V. All rights reserved.

Novel synthesised flavone derivatives provide significant insight into the structural features required for enhanced anti-proliferative activity

With many cancers showing resistance to current chemotherapies, the search for novel anti-cancer agents is attracting considerable attention. Natural flavonoids have been identified as useful leads in such programmes. However, since an in-depth understanding of the structural requirements for optimum activity is generally lacking, further research is required before the full potential of flavonoids as anti-proliferative agents can be realised. Herein a broad library of 76 methoxy and hydroxy flavones, and their 4-thio analogues, was constructed and their structure-activity relationships for anti-proliferative activity against the breast cancer cell lines MCF-7 (ER+ve), MCF-7/DX (ER+ve, anthracycline resistant) and MDA-MB-231 (ER-ve) were probed. Within this library, 42 compounds were novel, and all compounds were afforded in good yields and > 95% purity. The most promising lead compounds, specifically the novel hydroxy 4-thioflavones 15f and 16f, were further evaluated for their anti-proliferative activities against a broader range of cancer cell lines by the National Cancer Institute (NCI), USA and displayed significant growth inhibition profiles (e.g Compound-15f: MCF-7 (GI50 = 0.18 μM), T-47D (GI50 = 0.03 μM) and MDA-MB-468 (GI50 = 0.47 μM) and compound-16f: MCF-7 (GI50 = 1.46 μM), T-47D (GI50 = 1.27 μM) and MDA-MB-231 (GI50 = 1.81 μM). Overall, 15f and 16f exhibited 7-46 fold greater anti-proliferative potency than the natural flavone chrysin (2d). A systematic structure-activity relationship study against the breast cancer cell lines highlighted that free hydroxyl groups and the B-ring phenyl groups were essential for enhanced anti-proliferative activities. Substitution of the 4-C=O functionality with a 4-C=S functionality, and incorporation of electron withdrawing groups at C4’ of the B-ring phenyl, also enhanced activity. Molecular docking and mechanistic studies suggest that the anti-proliferative effects of flavones 15f and 16f are mediated via ER-independent cleavage of PARP and downregulation of GSK-3β for MCF-7 and MCF-7/DX cell lines. For the MDA-MB-231 cell line, restoration of the wild-type p53 DNA binding activity of mutant p53 tumour suppressor gene was indicated.

A semi-quantitative approach to deriving a model structure for the uptake of organic chemicals by vegetation

An expert elicitation exercise was undertaken to determine those components and processes that are most important for modeling plant uptake of organic chemicals. The state of our knowledge of these processes was also assessed. This semi-quantitative analysis allowed the construction of an idealized model with seven compartments; soil bulk, soil water, roots, stem, leaves, fruit, and air. Three main areas were identified further research: 1) the uptake of organic chemicals by fruit; 2) the internal transfer of organic chemicals between plant structures (e.g., stem and leaves); and 3) the transfer via the soil-air-plant pathway. Until new data becomes available to quantify these processes, it is proposed that an equilibrium partitioning approach is used between plant components other than fruit or that models consist of both an edible and inedible compartment.

Macrophyte community structure and species occurrence in relation to environmental determinants in the ephemeral aquatic habitats of Gavdos, Greece

The aims of this study were to explore the environmental factors that determine the distribution of plant communities in temporary rock pools and provide a quantitative analysis of vegetation-environment relationships for five study sites on the island of Gavdos, southwest of Crete, Greece. Data from 99 rock pools were collected and analysed using Two-Way Indicator Species Analysis (TWINSPAN), Detrended Correspondence Analysis (DCA) and Canonical Correspondence Analysis (CCA) to identify the principal communities and environmental gradients that are linked to community distribution. A total of 46 species belonging to 21 families were recorded within the study area. The dominant families were Labiatae, Gramineae and Compositae while therophytes and chamaephytes were the most frequent life forms. The samples were classified into six community types using TWINSPAN, which were also corroborated by CCA analysis. The principal gradients for vegetation distribution, identified by CCA, were associated with water storage and water retention ability, as expressed by pool perimeter and water depth. Generalised Additive Models (GAMs) were employed to identify responses of four dominant rock pool species to water depth. The resulting species response curves showed niche differentiation in the cases of Callitriche pulchra and Tillaea vaillantii and revealed competition between Zannichellia pedunculata and Chara vulgaris. The use of classification in combination with ordination techniques resulted in a good discrimination between plant communities. Generalised Additive Models are a powerful tool in investigating species response curves to environmental gradients. The methodology adopted can be employed for improving baseline information on plant community ecology and distribution in Mediterranean ephemeral pools.

Morphological and physiological changes induced by high hydrostatic pressure in exponential- and stationary-phase cells of Escherichia coli: relationship with cell death

The relationship between a loss of viability and several morphological and physiological changes was examined with Escherichia coli strain J1 subjected to high-pressure treatment. The pressure resistance of stationary-phase cells was much higher than that of exponential-phase cells, but in both types of cell, aggregation of cytoplasmic proteins and condensation of the nucleoid occurred after treatment at 200 MPa for 8 min. Although gross changes were detected in these cellular structures, they were not related to cell death, at least for stationary-phase cells. In addition to these events, exponential-phase cells showed changes in their cell envelopes that were not seen for stationary-phase cells, namely physical perturbations of the cell envelope structure, a loss of osmotic responsiveness, and a loss of protein and RNA to the extracellular medium. Based on these observations, we propose that exponential-phase cells are inactivated under high pressure by irreversible damage to the cell membrane. In contrast, stationary-phase cells have a cytoplasmic membrane that is robust enough to withstand pressurization up to very intense treatments. The retention of an intact membrane appears to allow the stationary-phase cell to repair gross changes in other cellular structures and to remain viable at pressures that are lethal to exponential-phase cells.

A flow system for the on-line quantitative measurement of the retention of dosage forms on biological surfaces using spectroscopy and image analysis

Measuring the retention, or residence time, of dosage forms to biological tissue is commonly a qualitative measurement, where no real values to describe the retention can be recorded. The result of this is an assessment that is dependent upon a user's interpretation of visual observation. This research paper outlines the development of a methodology to quantitatively measure, both by image analysis and by spectrophotometric techniques, the retention of material to biological tissues, using the retention of polymer solutions to ocular tissue as an example. Both methods have been shown to be repeatable, with the spectrophotometric measurement generating data reliably and quickly for further analysis.

Structure of turbulent flow over arrays of cubical roughness

The structure of turbulent flow over large roughness consisting of regular arrays of cubical obstacles is investigated numerically under constant pressure gradient conditions. Results are analysed in terms of first- and second-order statistics, by visualization of instantaneous flow fields and by conditional averaging. The accuracy of the simulations is established by detailed comparisons of first- and second-order statistics with wind-tunnel measurements. Coherent structures in the log region are investigated. Structure angles are computed from two-point correlations, and quadrant analysis is performed to determine the relative importance of Q2 and Q4 events (ejections and sweeps) as a function of height above the roughness. Flow visualization shows the existence of low-momentum regions (LMRs) as well as vortical structures throughout the log layer. Filtering techniques are used to reveal instantaneous examples of the association of the vortices with the LMRs, and linear stochastic estimation and conditional averaging are employed to deduce their statistical properties. The conditional averaging results reveal the presence of LMRs and regions of Q2 and Q4 events that appear to be associated with hairpin-like vortices, but a quantitative correspondence between the sizes of the vortices and those of the LMRs is difficult to establish; a simple estimate of the ratio of the vortex width to the LMR width gives a value that is several times larger than the corresponding ratio over smooth walls. The shape and inclination of the vortices and their spatial organization are compared to recent findings over smooth walls. Characteristic length scales are shown to scale linearly with height in the log region. Whilst there are striking qualitative similarities with smooth walls, there are also important differences in detail regarding: (i) structure angles and sizes and their dependence on distance from the rough surface; (ii) the flow structure close to the roughness; (iii) the roles of inflows into and outflows from cavities within the roughness; (iv) larger vortices on the rough wall compared to the smooth wall; (v) the effect of the different generation mechanism at the wall in setting the scales of structures.