Correlation-type structure activity relationships for the kinetics of gas-phase RO2 self-reactions and reaction with HO2

Structure activity relationships (SARs) are presented for the gas-phase reactions of RO2 with HO2, and the self- and cross-reactions of RO2. For RO2+HO2 the SAR is based upon a correlation between the logarithm of the measured rate coefficient and a calculated ionisation potential for the molecule R-CH=CH2, R being the same group in both the radical and molecular analogue. The correlation observed is strong and only for one RO2 species does the measured rate coefficient deviate by more than a factor of two from the linear least-squares regression line. For the self- and cross-reactions of RO2 radicals, the SAR is based upon a correlation between the logarithm of the measured rate coefficient and the calculated electrostatic potential (ESP) at the equivalent carbon atom in the RH molecule to which oxygen is attached in RO2, again R being the same group in the molecule and the radical. For cases where R is a simple alkyl-group, a strong linear correlation observed. For RO2 radicals which contain lone pair-bearing substituents and for which the calculated ESP<-0.05 self-reaction rate coefficients appear to be insensitive to the value of the ESP. For RO2 of this type with ESP>-0.05 a linear relationship between log k and the ESP is again observed. Using the relationships, 84 out of the 85 rate coefficients used to develop the SARs are predicted to within a factor of three of their measured values. A relationship is also presented that allows the prediction of the Arrhenius parameters for the self-reactions of simple alkyl RO2 radicals. On the basis of the correlations, predictions of room-temperature rate coefficients are made for a number of atmospherically important peroxyl-peroxyl radical reactions. (C) 2003 Elsevier Ltd. All rights reserved.

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.

Gas-phase rate coefficients for reactions of NO3, OH, O-3 and O(P-3) with unsaturated alcohols and ethers: correlations and structure-activity relations (SARs)

Experimental difficulties sometimes force modellers to use predicted rate coefficients for reactions of oxygenated volatile organic compounds (oVOCs). We examine here methods for making the predictions for reactions of atmospheric initiators of oxidation, NO3, OH, O-3 and O(P-3), with unsaturated alcohols and ethers. Logarithmic correlations are found between measured rate coefficients and calculated orbital energies, and these correlations may be used directly to estimate rate coefficients for compounds where measurements have not been performed. To provide a shortcut that obviates the need to calculate orbital energies, structure-activity relations (SARs) are developed. Our SARs are tested for predictive power against compounds for which experimental rate coefficients exist, and their accuracy is discussed. Estimated atmospheric lifetimes for oVOCs are presented. The SARs for alkenols successfully predict key rate coefficients, and thus can be used to enhance the scope of atmospheric models incorporating detailed chemistry. SARs for the ethers have more limited applicability, but can still be useful in improving tropospheric models. (C) 2008 Elsevier Ltd. All rights reserved.

Gas-phase rate coefficients for the reactions of NO3, OH and O-3 with alpha,beta-unsaturated esters and ketones: structure-activity relations (SARs)

Gas-phase rate coefficients for the atmospherically important reactions of NO3, OH and O-3 are predicted for 55 alpha,beta-unsaturated esters and ketones. The rate coefficients were calculated using a correlation described previously [Pfrang, C., King, M.D., C. E. Canosa-Mas, C.E., Wayne, R.P., 2006. Atmospheric Environment 40, 1170-1179]. These rate coefficients were used to extend structure-activity relations for predicting the rate coefficients for the reactions of NO3, OH or O-3 with alkenes to include alpha,beta-unsaturated esters and ketones. Conjugation of an alkene with an alpha,beta-keto or alpha,beta-ester group will reduce the value of a rate coefficient by a factor of similar to 110, similar to 2.5 and similar to 12 for reaction with NO3, OH or O-3, respectively. The actual identity of the alkyl group, R, in -C(O)R or -C(O)OR has only a small influence. An assessment of the reliability of the SAR is given that demonstrates that it is useful for reactions involving NO3 and OH, but less valuable for those of O-3 or peroxy nitrate esters. (c) 2006 Elsevier Ltd. All rights reserved.

Synthesis of heterosulfamates. Search for structure-taste relationships

Thirty one new sodium heterosulfamates, RNHSO3Na, where the R portion contains mainly thiazole, benzothiazole, thiadiazole and pyridine ring structures, have been synthesized and their taste portfolios have been assessed. A database of 132 heterosulfamates ( both open-chain and cyclic) has been formed by combining these new compounds with an existing set of 101 heterosulfamates which were previously synthesized and for which taste data are available. Simple descriptors have been obtained using (i) measurements with Corey-Pauling-Koltun (CPK) space- filling models giving x, y and z dimensions and a volume VCPK, (ii) calculated first order molecular connectivities ((1)chi(v)) and (iii) the calculated Spartan program parameters to obtain HOMO, LUMO energies, the solvation energy E-solv and V-SPART AN. The techniques of linear (LDA) and quadratic (QDA) discriminant analysis and Tree analysis have then been employed to develop structure-taste relationships (SARs) that classify the sweet (S) and non-sweet (N) compounds into separate categories. In the LDA analysis 70% of the compounds were correctly classified ( this compares with 65% when the smaller data set of 101 compounds was used) and in the QDA analysis 68% were correctly classified ( compared to 80% previously). TheTree analysis correctly classified 81% ( compared to 86% previously). An alternative Tree analysis derived using the Cerius2 program and a set of physicochemical descriptors correctly classified only 54% of the compounds.

The physics of baking: rheological and polymer molecular structure-function relationships in breadmaking

Molecular size and structure of the gluten polymers that make up the major structural components of wheat are related to their rheological properties via modem polymer rheology concepts. Interactions between polymer chain entanglements and branching are seen to be the key mechanisms determining the rheology of HMW polymers. Recent work confirms the observation that dynamic shear plateau modulus is essentially independent of variations in MW amongst wheat varieties of varying baking performance and is not related to variations in baking performance, and that it is not the size of the soluble glutenin polymers, but the structural and rheological properties of the insoluble polymer fraction that are mainly responsible for variations in baking performance. The rheological properties of gas cell walls in bread doughs are considered to be important in relation to their stability and gas retention during proof and baking, in particular their extensional strain hardening properties. Large deformation rheological properties of gas cell walls were measured using biaxial extension for a number of doughs of varying breadmaking quality at constant strain rate and elevated temperatures in the range 25-60 degrees C. Strain hardening and failure strain of cell walls were both seen to decrease with temperature, with cell walls in good breadmaking doughs remaining stable and retaining their strain hardening properties to higher temperatures (60 degrees C), whilst the cell walls of poor breadmaking doughs became unstable at lower temperatures (45-50 degrees C) and had lower strain hardening. Strain hardening measured at 50 degrees C gave good correlations with baking volume, with the best correlations achieved between those rheological measurements and baking tests which used similar mixing conditions. As predicted by the Considere failure criterion, a strain hardening value of I defines a region below which gas cell walls become unstable, and discriminates well between the baking quality of a range of commercial flour blends of varying quality. This indicates that the stability of gas cell walls during baking is strongly related to their strain hardening properties, and that extensional rheological measurements can be used as predictors of baking quality. (C) 2004 Elsevier B.V. All rights reserved.

The physics of baking: rheological and polymer molecular structure-function relationships in breadmaking

Molecular size and structure of the gluten polymers that make up the major structural components of wheat are related to their rheological properties via modern polymer rheology concepts. Interactions between polymer chain entanglements and branching are seen to be the key mechanisms determining the rheology of HMW polymers. Recent work confirms the observation that dynamic shear plateau modulus is essentially independent of variations in MW amongst wheat varieties of varying baking performance and is not related to variations in baking performance, and that it is not the size of the soluble glutenin polymers, but the structural and rheological properties of the insoluble polymer fraction that are mainly responsible for variations in baking performance. The rheological properties of gas cell walls in bread doughs are considered to be important in relation to their stability and gas retention during proof and baking, in particular their extensional strain hardening properties. Large deformation rheological properties of gas cell walls were measured using biaxial extension for a number of doughs of varying breadmaking quality at constant strain rate and elevated temperatures in the range 25oC to 60oC. Strain hardening and failure strain of cell walls were both seen to decrease with temperature, with cell walls in good breadmaking doughs remaining stable and retaining their strain hardening properties to higher temperatures (60oC), whilst the cell walls of poor breadmaking doughs became unstable at lower temperatures (45oC to 50oC) and had lower strain hardening. Strain hardening measured at 50oC gave good correlations with baking volume, with the best correlations achieved between those rheological measurements and baking tests which used similar mixing conditions. As predicted by the Considere failure criterion, a strain hardening value of 1 defines a region below which gas cell walls become unstable, and discriminates well between the baking quality of a range of commercial flour blends of varying quality. This indicates that the stability of gas cell walls during baking is strongly related to their strain hardening properties, and that extensional rheological measurements can be used as predictors of baking quality.

Gas-phase rate coefficients for the reactions of O(3P), S(3P), Se(3P), and Te(3P) with alkenes: application of perturbation frontier molecular orbital theory, correlations, and structure-activity relations (SARs)

The kinetics of the reactions of the atoms O(P-3), S(P-3), Se(P-3), and Te((3)p) with a series of alkenes are examined for correlations relating the logarithms of the rate coefficients to the energies of the highest occupied molecular orbitals (HOMOs) of the alkenes. These correlations may be employed to predict rate coefficients from the calculated HOMO energy of any other alkene of interest. The rate coefficients obtained from the correlations were used to formulate structure-activity relations (SARs) for reactions of O((3)p), S(P-3), Se (P-3), and Te((3)p) with alkenes. A comparison of the values predicted by both the correlations and the SARs with experimental data where they exist allowed us to assess the reliability of our method. We demonstrate the applicability of perturbation frontier molecular orbital theory to gas-phase reactions of these atoms with alkenes. The correlations are apparently not applicable to reactions of C(P-3), Si(P-3), N(S-4), and Al(P-2) atoms with alkenes, a conclusion that could be explained in terms of a different mechanism for reaction of these atoms.

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.

Structure property relationships in electrically conducting copolymers formed from pyrrole and N-methyl pyrrole

A series of copolymers containing differing proportions of pyrrole and N-methyl pyrrole were prepared electrochemically at various temperatures using acetonitrile as the solvent. The resultant electrical conductivity decreases universally with increasing fraction of N-methyl pyrrole. Films prepared with p-toluene sulfonate as the dopant show a marked variation in structural anisotropy as revealed by X-ray scattering with apparent copolymer content. There is a clear trend between the variation in electrical conductivity and this structural anisotropy. Different patterns of behaviour are observed for films prepared using perchlorate as the dopant and this is attributed to the role of the dopant and final structure in determining the relative reactivities of the pyrrole and N-methyl pyrrole monomers. These observations support the concept that the introduction of methyl substituents into a polypyrrole chain results in a twisted chain conformation. The structure and properties of the resultant copolymer films are particularly sensitive to the preparation conditions.

Heat treatment enhances the antimicrobial activity of (+)-Catechin when combined with copper sulphate

The aim of the study was to compare the antimicrobial activities of freshly-made, heat-treated (HT), and 14 d stored (+)-Catechin solutions with (+)-catechin flavanol isomers in the presence of copper sulphate. (+)-Catechin activity was investigated when combined with different ratios of Cu2+; 100°C heat treatment; autoclaving; and 14 d storage against Staphylococcus aureus. Cu2+-(+)-Catechin complexation, isomer structure-activity relationships, and H2O2 generation were also investigated. Freshly-made, HT, and 14d stored flavanols showed no activity. Whilst combined Cu2+-autoclaved (+)-Catechin and -HT(+)-Catechin activities were similar, HT(+)-Catechin was more active than either freshly-made (+)-catechin (generating more H2O2) or (-)-Epicatechin (though it generated less H2O2) or 14d-(+)-Catechin (which had similar activity to Cu2+ controls - though it generated more H2O2). When combined with Cu2+, in terms of rates of activity, HT(+)-Catechin was lower than (-)-Epigallocatechin gallate and greater than freshly-made (+)-Catechin. Freshly-made and HT(+)-Catechin formed acidic complexes with Cu2+ as indicated by pH and UV-vis measurements although pH changes did not account for antimicrobial activity. Freshly-made and HT(+)-Catechin both formed Cu2+ complexes. The HT(+)-Catechin complex generated more H2O2 which could explain its higher antimicrobial activity.

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.

Unravelling the conundrum of tannins in animal nutrition and health

This paper examines the nutritional and veterinary effects of tannins on ruminants and makes some comparisons with non-ruminants. Tannin chemistry per se is not covered and readers are referred to several excellent reviews instead: (a) Okuda T et al. Heterocycles 30:1195-1218 (1990); (b) Ferreira D and Slade D. Nat Prod Rep 19:517-541 (2002); (c) Yoshida T et al. In Studies in Natural Product Chemistry. Elsevier Science, Amsterdam, pp. 395-453 (2000); (d) Khanbabaee K and van Ree T. Nat Prod Rep 18:641-649 (2001); (e) Okuda et al. Phytochemistvy 55:513-529 (2000). The effects of tannins on rumen micro-organisms are also not reviewed, as these have been addressed by others: (a) McSweeney CS et al. Anim Feed Sci Technol 91:83-93 (2001); (b) Smith AH and Mackie RI. Appl Environ Microbiol 70:1104-1115 (2004). This paper deals first with the nutritional effects of tannins in animal feeds, their qualitative and quantitative diversity, and the implications of tannin-protein complexation. It then summarises the known physiological and harmful effects and discusses the equivocal evidence of the bioavailability of tannins. Issues concerning tannin metabolism and systemic effects are also considered. Opportunities are presented on how to treat feeds with high tannin contents, and some lesser-known but successful feeding strategies are highlighted. Recent research has explored the use of tannins for preventing animal deaths from bloat, for reducing intestinal parasites and for lowering gaseous ammonia and methane emissions. Finally, several tannin assays and a hypothesis are discussed that merit further investigation in order to assess their suitability for predicting animal responses. The aim is to provoke discussion and spur readers into new approaches. An attempt is made to synthesise the emerging information for relating tannin structures with their activities. Although many plants with high levels of tannins produce negative effects and require treatments, others are very useful animal feeds. Our ability to predict whether tannin-containing feeds confer positive or negative effects will depend on interdisciplinary research between animal nutritionists and plant chemists. The elucidation of tannin structure-activity relationships presents exciting opportunities for future feeding strategies that will benefit ruminants and the environment within the contexts of extensive, semi-intensive and some intensive agricultural systems. (c) 2006 Society of Chemical Industry

Unravelling the conundrum of tannins in animal nutrition and health

This paper examines the nutritional and veterinary effects of tannins on ruminants and makes some comparisons with non-ruminants. Tannin chemistry per se is not covered and readers are referred to several excellent reviews instead: (a) Okuda T et al. Heterocycles 30:1195-1218 (1990); (b) Ferreira D and Slade D. Nat Prod Rep 19:517-541 (2002); (c) Yoshida T et al. In Studies in Natural Product Chemistry. Elsevier Science, Amsterdam, pp. 395-453 (2000); (d) Khanbabaee K and van Ree T. Nat Prod Rep 18:641-649 (2001); (e) Okuda et al. Phytochemistvy 55:513-529 (2000). The effects of tannins on rumen micro-organisms are also not reviewed, as these have been addressed by others: (a) McSweeney CS et al. Anim Feed Sci Technol 91:83-93 (2001); (b) Smith AH and Mackie RI. Appl Environ Microbiol 70:1104-1115 (2004). This paper deals first with the nutritional effects of tannins in animal feeds, their qualitative and quantitative diversity, and the implications of tannin-protein complexation. It then summarises the known physiological and harmful effects and discusses the equivocal evidence of the bioavailability of tannins. Issues concerning tannin metabolism and systemic effects are also considered. Opportunities are presented on how to treat feeds with high tannin contents, and some lesser-known but successful feeding strategies are highlighted. Recent research has explored the use of tannins for preventing animal deaths from bloat, for reducing intestinal parasites and for lowering gaseous ammonia and methane emissions. Finally, several tannin assays and a hypothesis are discussed that merit further investigation in order to assess their suitability for predicting animal responses. The aim is to provoke discussion and spur readers into new approaches. An attempt is made to synthesise the emerging information for relating tannin structures with their activities. Although many plants with high levels of tannins produce negative effects and require treatments, others are very useful animal feeds. Our ability to predict whether tannin-containing feeds confer positive or negative effects will depend on interdisciplinary research between animal nutritionists and plant chemists. The elucidation of tannin structure-activity relationships presents exciting opportunities for future feeding strategies that will benefit ruminants and the environment within the contexts of extensive, semi-intensive and some intensive agricultural systems. (c) 2006 Society of Chemical Industry