bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Optimization of a PSI Electron‐Accepting 1,2,4‐Benzotriazine Herbicide
Authors: Henrie Robert N. , Plummer Marjorie J. , Smith Sandra E. , Yeager Walter H. , Witkowski Debra A. 
Published: October 2006

AbstractA random source PSI electron‐accepting herbicide lead, ethyl 1,2,4‐benzotriazine‐3‐acetate 1, was optimized using molecular probing, bioisosteric replacement, Free‐Wilson analysis, Sequential Simplex Optimization, and ultimately linear regression analysis. Some variables in the initial regression equations were found to be cross correlated, representing the same factors as revealed by factor analysis. The technique of prefiltering potential variables for linear regression analysis utilizing factor analysis is exemplified. For the set of 1 analogs, eleven independent factors were identified which were then submitted to linear regression analysis. The resulting equations are statistically more secure, all terms being independent. These equations are discussed in the context of known SAR for herbicidal PSI electron acceptors, especially the bipyridiniums.
New Trends in Structure‐Biodegradability Relationships
Authors: Cambon Benoit , Devillers James 
Published: October 2006

AbstractProblems related to structure‐biodegradation models are discussed. They deal with the homogeneity of the data sets, the selection of an adequate statistical method, and the choice of the molecular descriptors. This short review shows that the Boolean backpropagation neural networks are promising tools to model biodegradation. To confirm this hypothesis, a heterogeneous learning set of 47 molecules and two testing sets of 23 and 17 chemicals weakly (0) or highly (1) biodegradable are described by means of 11 Boolean structural descriptors. A supervised neural network using the backpropagation algorithm generates 100% and 85% of good predictions for the learning and testing sets, respectively. The results obtained are compared with those obtained from classical regression analysis. Advantages of this new approach are given. A particular application of correspondence factor analysis is presented to transform the Boolean variables before their introduction in the neural network. Advantages of this statistical transformation are stressed.
Multivariate Free‐Wilson Analysis of Some N‐Alkylmorphinan‐6‐one Opioids Using PLS
Authors: Norinder Ulf 
Published: October 2006

AbstractThe PLS method is used to derive an improved, unified and statistically significant Free‐Wilson QSAR model for the analgesic potency of some N‐alkylmorphinan‐6‐one opioids by the inclusion of a large number of first order cross‐terms between the substituents.To obtain high potency the R1/R2 substituent‐pair should be a cyclo‐butyl and a hydrogen (fenol), respectively, while the R3 substituent can be either an oxygen or a methylene bridge. The R4− and R5 substituents can both be a hydrogen or a methyl group to retain high potency of the opioids. Contrary to this, the R1/R2 pairs cyclo‐propyl/hydrogen and cyclo‐butyl/methyl as well as a n‐propyl substituent in the R5 position are quite unfavorable in this respect.
D‐Optimal Designs in QSAR
Authors: Baroni Massimo , Clementi Sergio , Cruciani Gabriele , Kettaneh‐Wold Nouna , Wold Svante 
Published: October 2006

AbstractStatistical design in principal properties based on D‐optimality criteria are particularly appropriate for selecting the most informative molecules to be synthesized and tested in the framework of QSAR studies. Selection by D‐optimal designs are better than those based on fractional factorial designs since they allow one to reduce the number of required structures, to reduce polysubstitution, to exclude molecules too difficult to synthesize and to include molecules already available and/or tested.
QSAR Study of Heteroaromatic Modifications in the Side Chain of Bradycardic Benzazepinones by Response Surface Modelling [1]
Authors: Musumarra Giuseppe , Stella Mario 
Published: October 2006

AbstractA literature data set on the bradycardic and hypotensive activities of benzazepinones with different monocyclic and bicyclic heteroaromatic moieties in the side chain was used to test the newly derived aromaticity principal properties (PP) descriptors in single parameter correlations showing that the logarithm of the bradycardic activity is related to “magnetic” aromaticity (the second heteroaromatic PP), while the hypotensive effect is related to “classical” aromaticity (the first heteroaromatic PP). The biological properties of the “optimum” compound combining high bradycardic potency, short duration of action and high selectivity versus hypotensive effects, were modelled by PLS response surfaces in terms of heteroaromatic moieties PP and C‐13 NMR shift of the attached carbon by means of the CARSO procedure. The models allow the rationalization of the biological properties and the detection of optimal heteroaromatics compatible with the overall desired biological behaviour.
Linear Solvation Energy Relationships in Reversed‐Phase Liquid Chromatography. Examination of Deltabond C8 as Stationary Phase for Measuring Lipophilicity Parameters
Authors: Altomare Cosimo , Cellamare Saverio , Carotti Angelo , Ferappi Marcello 
Published: October 2006

AbstractThe lipophilicity of a large set of solutes was measured by reversed‐phase high‐performance liquid chromatography, using a novel stationary phase, namely Deltabond C8 (DB), proposed to eliminate secondary adsorptive interactions. DB lipophilicity parameters have been found fairly well correlated with 1‐octanol‐water partition coefficients and a Linear Solvation Energy Relationship study has revealed that cavity term (modeled by intrinsic molar volume, VI) and hydrogen‐bond acceptor capacity (modeled by the solvatochromic parameter β) of solutes are the most important factors affecting retention on Deltabond C8. Compared with other reversed phases, DB allowed to determine retention data with a significant time saving and yielded lipophilicity parameters less affected by interactions with silanols.
Estimation of Electron Affinity Based on Structure Activity Relationships
Authors: Hilal S. H. , Carreira L. A. , Karickhoff S. W. , Melton C. M. 
Published: October 2006

AbstractElectron affinity for a wide range of organic molecules was calculated from molecular structure using the chemical reactivity models developed in SPARC. These models are based on fundamental chemical structure theory applied to the prediction of chemical reactivities for organic molecules strictly from molecular structure. The energy differences between the LUMO state and the HOMO state for a molecule of interest are factored into mechanistic components including the field, sigma induction and resonance contributions to these energy differences. The RMS deviation between observed and calculated electron affinities was found to be less than 0.14 e.v. for a large set of organic molecules.
Limitations of Functional‐Link Nets as Applied to QSAR Data Analysis
Authors: Manallack David T. , Livingstone David J. 
Published: October 2006

AbstractThis report compares the results of QSAR analyses examining a series of bis(1‐aziridinyl)‐p‐benzoquinones using multiple linear regression (MLR), neural networks and a network hybrid technique known as a functional‐link net (FUNCLINK). The FUNCLINK approach generates an expanded list of new parameters and seemed to outperform MLR as well as providing an apparently superior predictive ability. One observation from this work showed that neural networks generated higher correlation coefficients than MLR. This phenomenon, however, may be due to the inability of neural networks to predict values beyond their operating range. On examination of the results it appears that there are two disadvantages to the FUNCLINK technique. Firstly, the natural ability of neural networks to develop non‐linear relationships is removed with FUNCLINK as these must be specified. Secondly, the large number of enhanced parameters produced by FUNCLINK must increase the possibility of chance effects. From the results presented here it would appear that FUN‐CLINK adds little to the field of QSAR data analysis.
SmilogP: A Program for a Fast Evaluation of Theoretical Log P from the Smiles Code of a Molecule
Authors: Convard Thierry , Dubost Jean‐Pierre , Le Solleu H. , Kummer E. 
Published: October 2006

AbstractWe present here a software that generates an extended connectivity matrix from the SMILES code of a molecule. This extended connectivity matrix allows the determination of the atomic code for an atomic fragment and then the attribution of its lipophilicity contribution fi. Then, log P can be easily computed by summing the fi values. This program which runs on IBM PC or compatible systems, can be used by chemists or pharmaco chemists interested in the fast evaluation of the lipophilicity of a series of molecules.
Decomposition of Time Dependent Response Data by Factor Analysis
Authors: Franke Rainer , Gruska Andreas 
Published: October 2006

AbstractData on the analgesic potency of fentanyl derivatives measured at 10 different times (van Bever et al., 1976) were submitted to a factor analysis in comparison with results obtained by Balaz et al. with the help of a model based disposition function. Two significant factors are obtained which account for 80.6% and 17.9% of variance, respectively (total: 98.5%). The results are consistent with the hypothesis that the first factor can be attributed to pharmacokinetic processes to the binding site. The first factor is related to hydrophobicity in accordance with the pharmacokinetic model of Balaz et al. Affinity as expressed by the second factor can be modeled by Free‐Wilson analysis. Considering the factors it is possible to select results from two particular times of measurement for which meaningful QSARs for drug‐receptor interactions should also be derivable. These QSARs are again derived by means of Free‐Wilson analysis with statistically highly significant results. As predicted all other measurements did not lead to a significant solution. Factor analysis is a powerful tool to investigate quantitative structure‐time‐activity relationships in a model‐free manner.
Combined Use of Factorial Design and Comparative Molecular Field Analysis (CoMFA): a Case Study
Authors: Caliendo Giuseppe , Greco Giovanni , Novellino Ettore , Perissutti Elisa , Santagada Vincenzo 
Published: October 2006

AbstractThe factorial design (FD) strategy has been applied within the CoMFA framework to a set of 71 N‐acyl‐L‐aminoacid esters undergoing hydrolysis by α‐chymotripsin. The steric and electrostatic fields of the molecules aligned in their enzyme‐bound conformations have been subjected to Principle Component Analysis (PCA) and three latent variables have been extracted to build up an FD scheme. Two different training sets of 12 compounds have been formed which satisfy the FD criteria. In addition to these two rationally designed series, 50 training sets of 12 structures have been defined through a random selection procedure.A CoMFA model has been derived from each training set by correlating the binding affinity to the enzyme with the ligands' steric and electrostatic fields. The efficiency of the FD approach versus a simple random selection of the structures has been finally assessed by comparing the performances of the different CoMFA models in predicting the binding affinity of 59 ligands not belonging to the training set under consideration. Our results show that in absence of a proper series design strategy the risk of deriving a poorly predictive CoMFA model cannot be neglected.
The EDISFAR Programs. Drug Series Design in Polysubstituted Prototypes
Authors: Pastor Manuel , Alvarez‐Builla Julio 
Published: October 2006

AbstractLimitations of drug series design techniques are discussed. An original methodology based in factorial design, devoted to series design of polysubstituted compounds, is proposed. The application of this approach is illustrated by retrospective series design on two examples taken from literature, the last one involving a model with sum terms.
Comparative Molecular Field Analysis of Hydrophobicity Descriptors of Cytosine Nucleosides
Authors: Nicklaus Marc C. , Ford Harry , Hegedũs Lajos , Milne George W. A. , Kelley James A. 
Published: October 2006

AbstractComparative Molecular Field Analysis (CoMFA) was carried out on ten cytidine analogs that have been previously studied in the context of antitumor and antiviral activity. Quantitative structure‐property relationships (QSPR) were derived for measured octanol/water partition coefficients (logP) and reversed phase HPLC (RP‐HPLC) capacity factors (logkw′) by correlating these physicochemical properties with the three‐dimensional steric and electrostatic fields of the molecules. CoMFA QSPR models could be obtained with a maximum cross‐validatedr2= 0.778 for logPand a maximum cross‐validatedr2= 0.589 for logkw′. The best CoMFA models were obtained at an overwhelming relative electrostatic contribution for logP, and even more so for logkw′. The study revealed a great variation in the quality of the CoMFA QSPR models depending on the strategies and settings used when running the program. The settings employed allowed CoMFA to sample lattice points closer to the centers or the atoms than would be the case with the default settings, and thus to detect the presence of (charged) atoms rather than the fields surrounding them. The experimental logPvalues of ara‐cyclopentenylcytosine, 2′‐deoxycyclopentenylcytosine, carbodine, and isocarbodine are reported here for the first time.
Free‐Wilson Discriminant Analysis of Antiarrhythmic Phenylpyridines Using PLS
Authors: Hasegawa Kiyoshi , Shigyou Hiromichi , Sonoki Hiroyuki , Miyashita Yoshikastu , Sasaki Shin‐Ichi 
Published: October 2006

AbstractPLS modelling of antiarrhythmic activity of phenylpyridines based on the Free‐Wilson descriptor matrix is described. The Free‐Wilson descriptor matrix consists of fifteen columns for four substituents (R1, R2, R3 and R4). The contribution of structural fragments to the antiarrhythmic activity is examined by the MLR‐like model Eq. converted from the PLS model. The result corresponds with the previous PLS analysis of phenylpyridines and this correspondence implicitly validates the PLS analysis with the Free‐Wilson descriptor matrix used in this study.
Quantitative Structure‐Retention Relationships in Capillary Electrophoresis of Inorganic Cations and β‐Adrenolytic and Sulfonamides Compounds
Authors: Kaliszan Roman , Turowski Maciej , Buciñski A. , Hartwick Richard A. 
Published: October 2006

AbstractQuantitative structure‐(electrophoretic) retention relationships (QSRR) were determined for metal cations using ionic radius, atomic mass and ionization energy as structural parameters. The QSRR show that atomic mass, Am, can be treated as a descriptor of differences of electrophoretic retardation of inorganic cations. Am is a measure of the effective surface area of the solutes. The ionic radius of metals, Ir, accounts for the effective charge of a solute. The ionization energy, Ei, provides a correction to Ir with regard to solute charge. High predictive potency of QSRR and direct access to the required descriptors allow for the application of the approach in identification of individual components of mixtures of metals. In case of the capillary electrophoretic parameters of organic solutes molecular mass is a most significant retention descriptor identified. It can be considered a first approximation of the electrophoretic retardation factor. Further progress in QSRR in capillary electrophoresis of drugs requires reliable descriptors of effective charge of organic solutes.
Processes Underlying Interactions of Human Lactoferrin with the Jurkat Human Lymphoblastic T‐cell Line Receptor. I ‐ Quantitative Structure‐Affinity Relationships Studies
Authors: Elass Abdelaziz , Vergoten Gérard , Legrand Dominique , Mazurier Joël , Elass‐Rochard Elisabeth , Spik Geneviève 
Published: October 2006

AbstractHuman lactoferrin displays considerable structural homology with transferrins of other species. However, lactoferrins and transferrins play distinct biological roles and bind to specific cell receptors. Previous reports have shown that residues 4 ‐ 52 of human lactoferrin are potentially involved in interaction with a specific T‐lymphocyte receptor. In the present study, competitive binding assays of lactoferrin to the Jurkat human lymphoblastic T‐cell line were performed using seven lactoferrins and transferrins, as well as both C‐terminal lobes of human and bovine lactoferrins. Classical quantitative structure‐affinity relationships (QSAR) models revealed important descriptors, namely H‐bonds donor and acceptor groups of amino acid side chains, demonstrating that hydrogen bonding is a significant binding factor. This report points out the importance of residues R3, Q7, P14, N13, T17, F20, Q23, R24, K28, S38, D43, S44, P45, Q47, Q50 and N55 of human lactoferrin in the interaction with the lymphocyte receptor. The most important residues which contribute positively to the inhibition of the binding affinity are R3, Q7, Q23, R24, S38, the chemical groups involved in H‐bonding are R3‐(NH), Q7‐(=O), Q23‐(=O), R24‐(NH), S38‐(OH).
Modelling pKa of Carboxylic Acids and Chlorinated Phenols
Authors: Schürmann Gerrit 
Published: October 2006

AbstractEstimation of aqueous pKa through quantum chemical gas‐phase and solution‐phase calculations is investigated for 16 carboxylic acids and 15 phenols with experimental data taken from literature. Parameters based on the AM1 hamiltonian include enthalpy and free energy differences between the ground state of the ionizable compounds and their anion counterparts as well as respective transition states and intermediates along the reaction path of the aqueous proton transfer. With carboxylic acids, additional ab initio calculations are performed to evaluate the semiempirical level of theory. Aqueous solvation is modelled in three different ways: Application of continuum‐solvation methods AM1‐COSMO and AM1‐SM2, microsolvation of the solutes through formation of clusters with three water molecules, and combination of both approaches to include both bulk water polarization and solute‐solvent coupling effects. Regression equations with r values up to 0.93 for carboxylic acids and 0.96 for phenols suggest, that continuum‐solvation models can be recommended to estimate aqueous pKa through electronic structure calculations.
Quantitative Structure‐Activity Relationships of 5‐Lipoxygenase Inhibitors. Inhibitory Potency of Triazinone Analogues in a Broken Cell
Authors: Kim Ki H. , Martin Yvonne C. , Brooks Clint D. W. 
Published: October 2006

AbstractQuantitative structure‐activity relationships (QSAR) of sixty 1‐phenyl‐[2H]‐tetrahydrotriazin‐3‐one (I) analogues are examined for the inhibitory potency of 5‐lipoxygenase in a broken cell, IC50. Potency is increased by lipophilic substituents at the 3′‐, 5′‐, and 5‐positions. Potency is also increased with 3′‐ and 5′‐substituents that withdraw electrons and decreased with 3′,‐substituents on the pyridyl ring that donate electrons. On the other hand, the potency decreases as the size of 2′‐substituents increases. Thiourea analogues are about 1.6 times more potent than the corresponding carbonyl analogues.
Tyrosinase‐Mediated Cytotoxicity of 4‐Substituted Phenols: Use of QSAR to Forecast Reactivities of Thiols towards the Derivedortho‐Quinones
Authors: Cooksey Christopher J. , Land Edward J. , Rushton Francis A. P. , Ramsden Christopher A. , Riley Patrick A. 
Published: October 2006

AbstractCertain 4‐substituted phenols can behave as tyrosine analogues and undergo tyrosinase‐catalysed oxidation to cytotoxico‐quinones which react with crucial cellular thiols. Such phenols are potential melanogenesis‐specific pro‐drugs for the chemotherapy of malignant melanoma. Previously (Cookseyet al.(1995)Anti‐Cancer Drug Design,10, 119), by pulse radiolysis under oxidative conditions of the corresponding stable catechols in the presence and absence of thiols, we showed that the glutathione and cysteine reactivities of ten 4‐substitutedo‐quinones correlated well with the Hammett σpconstants of the corresponding substituents. Starting from the corresponding catechols, one of which has not previously been described, we have now investigated six further 4‐substitutedo‐quinones including two with substituent σpvalues higher than those previously studied. Extrapolation of the earlier quantitative structure ‐ activity relationships (QSAR) correctly predicted the high reactivities of these twoo‐quinones, with respective substituents OCF3and CH2NH3+, towards thiols. The data for all sixteen 4‐substitutedo‐quinones, and foro‐benzoquinone itself, have been combined to provide updated, statistically significant Hammett and Swain‐Lupton correlations, including multivariate regressions using the data for both thiols. These relationships show that in reacting the substitutedo‐quinones with thiols, the rate constants increase with the electron withdrawing capacities of the substituent groups, this being principally due to the resonance effect, with a smaller but significant contribution attributable to the field effect. Such QSAR may facilitate the design of improved melanogenesis ‐ targeted anti‐melanoma prodrugs.
Modelling In Vivo Human Skin Absorption
Authors: Hostýnek Jurij J. , Magee Philip S. 
Published: October 2006

AbstractWe correlated skin absorption data, determined in vivo in man under different experimental conditions for a set of 28 diverse chemical compounds, with experimental permeation constants (KpF) obtained for 8 compounds in vitro on human skin, and with the calculated Kp (Kp QSAR) according to a modified Potts‐Guy algorithm.Fick's first law of diffusion was applied to calculate in vivo penetration constants Kpmax at the point of maximum flux Jmax.The occlusion variable shows a positive coefficient linking the degree of occlusion to larger logJmax permeation rates. The most significant correlation is seen for a sub‐set of 10 semi‐occluded applications of different compounds, with an r = 0.83 for logKpmax vs. logKpQSAR, and a somewhat lower value r = 0.79 for logKpmax vs. logKpF. We could thus demonstrate that a pseudo‐steady state presents a valid alternative to infinite‐dose dermal absorption conditions or predicted permeation values, even though Fick's postulated steady state is not achieved and the maximum flux value, Jmax, is used instead.
Synthesis and Quality Control of Thiol Tagged Compound Libraries for Chemical Microarrays
Authors: Maier Sabine , Frank Michael , Rau Harald , Lewandrowski Peter , Uhrig Rainer , Keil Oliver , Deppe Holger , Müller Norbert , Vanier Cecile , Mannsperger Heiko , Zepter Siglinde , Junker Hans‐Dieter 
Published: October 2006

AbstractA method for the synthesis and quality control of compound collections containing reactive thiol functions was developed. Such libraries form the basis for the construction of chemical microarrays to be used in fragment‐based screening. Amino‐modified polymer membranes fixed into the wells of microtiter plates were used as the solid phase for the nanomole‐scale synthesis of a thiol‐tagged small molecule library using a spatial one‐compound/one‐well strategy. A thiolselective Liquid Chromatography‐Mass Spectroscopy (LC‐MS) protocol of each compound before attachment to the microarray surface was established, allowing an exact determination of compound purity and concentration. The established synthesis and quality control method is an important prerequisite for an accurate read‐out of the array compound–target interaction data, and simplifies the usage of small molecule microarrays for low affinity screening.