bluuebunny/crossref_metadata_2025 huggingface dataset:
Preliminary studies on the hydroalcoholic extract of the root of Cissampelos sympodialis Eichl in guinea‐pig tracheal strips and bronchoalveolar leucocytes
Authors: Thomas G. , Araújo C. C. , Agra M. De F. , Diniz M. De F. F. , Bachelet M. , Vargaftig B. B.
Published: October 2006

The aqueous fraction of the ethanol extract of the root of Cissampelos sympodialis, reduced the spontaneous tone, and inhibited the contractions induced by submaximal concentrations of carbachol, histamine, prostaglandin F2α and substance P, in guinea‐pig tracheal preparations. The fraction was approximately equipotent to aminophyl‐line and the IC50 values of the above agents varied from 13.9 to 95.5 μg/mL, depending on the agonist used. In concentrations ranging from 1–100 μg/mL, the fraction also increased the intracellular levels of cyclic adenosine monophosphate in guinea‐pig bronchoalveolar leucocytes. It is proposed that the combined effects on smooth muscles and on leucocytes indicate a pharmacological basis for the use of the plant in asthma.
Effect of picroliv on regeneration of liver after partial hepatectomy in rats
Authors: Saksena Seema , Rastogi Ravi , Garg N. K. , Dhawan B. N.
Published: October 2006

After partial hepatectomy in rats certain biochemical parameters in liver registered a maximal increase at varying periods of time, glutamate oxaloacetate transaminase (GOT), glutamate pyruvate transaminase (GPT) (6 h), lipid peroxides (12 h); DNA, RNA (24 h) and acid ribonuclease, acid phosphatase (48 h). In contrast, other parameters registered a maximal decrease after 6 h (glycogen) or 24 h (total proteins, cytochrome P450 and cytochrome b5). Subsequently, all these parameters started recovering towards their normal values which were attained in all parameters measured except RNA, glycogen, cytochrome h5 and acid ribonuclease. When partial hepatectomy was performed in rats fed 12 mg/kg body wt picroliv (an iridoid glycoside fraction of Picrorhiza kurroa) once daily for 7 days before killing, there was no significant difference in the time or degree of maximal changes but the rate of recovery in most of the biochemical parameters was faster. These results indicate that picroliv stimulated regeneration of liver.
Synthesis of [4,5‐3H]‐Exo‐3,6‐epoxyhexahydrophthatic anhydride
Authors: Wu Dezhu , Zheng Zongqi , Wang Guangsheng
Published: October 2006

A convenient two‐step synthesis of [4,5‐3H]‐Exo‐3,6‐epoxyhexahydrophthatic anhydride ((4,5‐3H)‐norcantharidin) consists of furan reacting with maleic anhydride to form dehydronorcantharidin. Then addition of tritium to dehydronorcantharidin with catalyst to form [4,5‐3H]‐norcantharidin. The specific activity and radiochemical purity were 56 Ci/mmol and 98%, respectively.
Antihistamine effects of an ethanol extract from the white petals of Impatiens balsamina L
Authors: Fukumoto Hisae , Isoi Koichiro , Semma Masanori , Ishiguro Kyoko
Published: October 2006

Using blood pressure (BP) monitoring in ddY Mice administered exogenous histamine, we tried to characterize the antianaphylactic mechanisms of a 35% ethanol extract (IB) from the petals of Impatiens balsamina L. Histamine was suggested to act as an initiator of anaphylactic hypotension in mice. IB could incompletely inhibit the first stage of hypotension caused by histamine. The antianaphylactic effect of IB was demonstrated to be different from that of diphenhydramine (DPH) a typical H1 blocker.
Spasmolytic actions of warifteine, a bisbenzylisoquinoline alkaloid isolated from the root bark of Cissampelos sympodialis Eichl. (menispermaceae)
Authors: de F. Cǒrtes S. , de Alencar J. L. , Thomas G. , Filho J. M. Barbosa
Published: October 2006

Warifteine, a bisbenzylisoquinoline alkaloid isolated from the root bark of Cissampelos sympodialis Eichl., produced a reversible, nonspecific and noncompetitive antagonism of histamine, carbachol and bradykinin induced contractions of the guinea‐pig ileum. The corresponding pD'2 values (mean±SE) were 4.90±0.15, 4.95±0.20 and 5.03±0.11. Warifteine also antagonized oxytocin and bradykinin induced contractions of the rat uterus in a similar manner with pD'2 values of 4.30±0.26 and 3.76±0.06 respectively. In the guinea‐pig trachea, the alkaloid inhibited spontaneous tone (IC50, 1.1 × 10−5M) as well as carbachol induced sustained contractions (IC50, 2.9 × 10−5M). As warifteine antagonized KCI induced contractions of the guinea‐pig ileum (pD'2 value 4.57±0.10), inhibition of Ca++ influx through voltage operated Ca++ channels may be partially responsible for its antispasmodic activity. However, the reported local anaesthetic property of warifteine may not contribute to the observed muscle relaxation as procaine failed to reduce the spontaneous tone or consistently antagonize carbachol induced contractions of the trachea and was inactive in inhibiting voltage operated Ca++ channels in the ileum.
A Free‐Wilson Analysis of 5β,14β‐Androstane Derivatives Inhibiting the Na/K‐ATPase from Human Heart
Authors: Schönfeld Werner , Repke Kurt R. H.
Published: October 2006

A Free‐Wilson analysis of 95 digitalis‐like steroids inhibiting the Na/K‐ATPase is presented. The chosen parent structure – 5β,14β‐androstane‐3β,14‐diol – was varied at 12 individual substitution sites. The high significance of the multiple regression of the data obtained with the great majority of the derivatives tested revealed the general applicability of the additivity model, allowing the prediction of the potency of hypothetical compounds from the derived 57de novosubstituent constants. Derivatives carrying voluminous substituents at C3 or C17, in which the cis/trans/cis‐junction of the steroid rings were altered, disclosed incompatibilities with the model.
Model‐Based Relation between Physicochemical Properties, Uptake and Uncoupling Effect of Carbonylcyanide Phenylhydrazones on Oxidative Phosphorylation at Cellular Level
Authors: Šturdik Ernest , Baláz Štefan , Ďurčová Edita , Šturdiková Mária , Sulo Pavol , Antalik Marián , Mikeš Vladimír , Dadák Vladimír
Published: October 2006

Analysis of uptake‐lipophilicity profiles of carbonylcyanide R‐phenylhydrazones (RC6H4NHNC(CN)2) in Paracoccus denitrificans and leukemic P‐388 cells showed that in early stages the drug distribution proceeds as simple diffusion in a multi‐phase system. After 10 min of partitioning only attainment of a lipophilic‐hydrophilic equilibrium was detected without observable chemical modification of the compounds. This fact allowed for straightforward formulation of two models for uncoupling of cellular oxidative phosphorylation, one based on protonophoric mechanism and the other involving covalent modification of energy transforming membrane proteins as the key step. Moreover, it enabled us to describe the dependence of uncoupling activity on lipophilicity using the uptake data and, thus, to reduce the number of adjustable parameters. The former (protonophoric) model exhibited a significantly better agreement with the experimental data in both biological systems.
QSAR and Multivariate Data Analysis of Amphiphilic Benzylamines and their Interaction with Various Phospholipids Determined by Different Methods
Authors: Seydel J. K. , Cordes H.‐P. , Wiese M. , Chi H. , Croes N. , Hanpft R. , Lüllmann H. , Mohr K. , Patten M. , Padberg Y. , Lüllmann‐Rauch R. , Vellguth S. , Meindl W. R. , Schönenberger H.
Published: October 2006

Amphiphilic drugs of various structures are known to interact with phospholipids. Simple benzylamines have been used as probes to test the structural influence on the degree of interaction. This interaction has been quantified with various methods as for example NMR‐binding measurements, scanning calorimetry, inhibition of Ca++‐incorporation, negative inotropic effect and antimycobacterial activity.

Multiregression and multivariate data analysis have been performed and the results are discussed.
Topological Indices in Correlation Analysis. Part 1. Comparison of Molecular Shape with Molecular Connectivity for Some Hydrocarbons
Authors: Mokrosz Jerzy L.
Published: October 2006

Two sets of the topological indices, i.e. molecular shape and molecular connectivity were calculated for a group of model hydrocarbons.

Intercorrelation between these indices for five different sets of compounds was discussed.
Hydrophobicity and Tumor Promoting Activity of Phorbol Esters
Authors: Rippmann Friedrich
Published: October 2006

Phorbol esters are polyfunctional agents which influence the carcinogenic process via a receptor mechanism. Two structural elements of phorbol esters seem to be responsible for tumor promoting activity. One element is formed of certain hydrophilic groups which are supposed to be responsible for the specific receptor binding. The other element consists of hydrophobic groups which should rather unspecifically be responsible for partition and transport between biological phases. In order to differentiate between these two structural elements, the numerical relativ tumor promoting activity of phorbol diesters (a new activity in QSAR) was calculated from rodent skin painting experiments and its dependence from hydrophobicity was modeled using the parabolic and the bilinear model. The results show that the tumor promoting activity of aliphatic phorbol 12,13‐diesters can adequately be described by hydrophobicity only. This indicates that the structural element aliphatic‐12,13‐diesters is rather unspecifically responsible for partition and transport between biological phases. A medium hydrophobicity caused by aliphatic ester chains in position 12 and 13 of phorbol is a sufficient condition for high promoting activity as long as the other hydrophilic groups are not removed, acylated or otherwise changed.
Pharmacophore Identification in Amnesia‐Reversal Compounds Using Conformational Analysis and Chemometric Methods
Authors: Cosentino Ugo , Moro Giorgio , Pitea Demetrio , Todeschini Roberto , Brossa Simonetta , Gualandi Federico , Scolastico Carlo , Giannessi Fabio
Published: October 2006

The conformational features of ten known amnesia reversal compounds were analyzed by the molecular mechanics calculations with the aim of identifying a common spatial disposition of the polar functional groups present in all the molecules (a N‐C=O amidic group and a X‐C=O group, with X = O, N). Principal component analysis (PCA) led to the identification of three interatomic distances able to provide all the information necessary to describe the relative spatial disposition of the two functional groups. Cluster analysis was then performed to group the minimum energy conformations according to the values of those distances. Clusters were analyzed to single out those containing conformations of the maximum number of active compounds. This procedure permitted the finding of several acceptable pharmacophore models. The influence on results by the dissociated/undissociated forms of carboxylic compounds presented in the data set is also discussed. Two potent prolyl endopeptidase (PEP) inhibitors showing strong anti‐amnesic effect were also included in the study. The results suggest that the common biological activity between these classes of compounds could be interpreted on the basis of the common spatial disposition of the investigated functional groups.
Induction of Cytochrome P450 by Barbiturates in Chick Embryo Hepatocytes: A Quantitative Structure‐Activity Analysis
Authors: Hansch Corwin , Sinclair Jacqueline F. , Sinclair Peter R.
Published: October 2006

In cultured chick embryo hepatocytes, induction of cytochrome P450 by nine 5,5‐substituted barbiturates was analyzed for a quantitative structure‐activity relationship. The data led to the following equation:
Log 1/C = 1.02 (±0.16) log P + 2.75 (±0.28), r = 0.984
where C is the concentration that caused a 50% increase in cytochrome P450, P is the partition coefficient between octanol and water, and r is the correlation coefficient. The results suggest that the potency of the barbiturates was directly related to their hydrophobicity.
Quantitative Structure‐Activity Relationship (QSAR) Studies Using Electronic Descriptors Calculated from Topological and Molecular Orbital (MO) Methods
Authors: Gombar Vijay K. , Enslein Kurt
Published: October 2006

The performance of certain electronic descriptors rapidly calculated by a topology‐based method has been compared with those computed by time‐consuming MO methods for QSAR studies on mutagenicity of a set of triazenes. The highly significant correlations obtained in the two cases not only are of excellently comparable statistical quality but also support the same mechanism of mutagenicity.
A Structure‐Activity Relationship for the Binding of Acridine‐4‐Carboxamides to DNA
Authors: Moyer Susan R. , Jurs Peter C.
Published: October 2006

The DNA binding constants for a series of acridine‐4‐carboxamides were modeled using quantitative structure‐activity relationship methodology. In particular, a data set containing 52 acridine derivatives along with their DNA binding constants for the poly(dA‐dT) and poly(dG‐dC) sites of DNA was obtained from the literature. The descriptors which were calculated and ultimately used in the regression models were designed to encode a specific binding site model which had previously been proposed in the literature. Since it is believed that the acridines interact with the DNA by intercalation, surface area and charge descriptors were calculated for regions of the acridine backbone which are theorized to be in close proximity to the DNA chain. The ability of these descriptors to successfully model the DNA binding constants for the data set supports the binding model which was previously proposed.
3‐Hydroxy‐3‐Methylglutaryl‐Coenzyme A Reductase: Molecular Modeling, Three‐Dimensional Structure‐Activity Relationships, Inhibitor Design
Authors: Motoc I. , Sit S. Y. , Harte W. E. , Balasubramanian N. , Wright J. J.
Published: October 2006

The 9,9‐bis(4‐fluorophenyl)‐3,5‐dihydroxy‐8‐(substituted)‐6, 8‐nonadienoic acid analogues represent a novel class of HMG‐CoA reductase inhibitors developed in our laboratories. We delineate from inhibitory potency values the main topographical and physicochemical features of the binding site probed by substituents attached to the C8 position of the analogues. Using a combination of receptor mapping and 3D‐QSAR techniques, it was possible to determine a logical candidate for the conformation of the inhibitor bound to the receptor and to derive a reliable 3D‐QSAR which relates the HMG‐CoA reductase inhibitory potency to the shape and size of both the binding site and C8‐substituent of the inhibitor. We show that the 3D‐QSAR derived here affords predictive utility.
Using Theoretical Descriptors in Quantitative Structure‐Activity Relationships: Comparison with the Molecular Transform
Authors: Famini George R. , Kassel Ronald J. , King James W. , Wilson Leland Y.
Published: October 2006

A variety of techniques and methodologies are currently being used in quantitative structure‐activity relationships (QSAR). A major difficulty with past relationships has been the use of a parameter sets which cannot be applied uniformly to a wide range of properties and data sets. The development of the Linear Solvation Energy Relationship by Kamlet and Taft, and our development of the Theoretical Linear Solvation Energy Relationship (TLSER) have attempted to overcome this principal difficulty by employing a standard parameter set for every correlation. Another methodology that has also proven successful in this regard is the use of topological indices to correlate a variety of properties. This paper compares the TLSER with one such index, the molecular transform. In addition, we show the high correlative capability of the TLSER methodology with the minimum blocking concentration for a set of 36 local anesthetics.
A QSAR Approach to the Study of Structural Requirements of Muscarinic Receptor Ligands Part I: Agonists
Authors: Pratesi P. , Caliendo G. , Silipo C. , Vittoria A.
Published: October 2006

This report examines the development of quantitative structure‐activity relationships (QSAR) in the analysis of ligand muscarinic receptor interactions. Several sets of agonists acting on different tissues (distinct receptor subtypes) are considered. It is shown that QSAR may represent a suitable tool to increase the general understanding of the nature of ligand interactions at receptor sites. The points discussed in the paper are to draw attention to the development of correlations between biological affinity constants and molecular architecture of the ligands which are essential for deriving refined concepts on the topology of muscarinic receptor sites.
A QSAR Approach to the Study of Structural Requirements of Muscarinic Receptor Ligands Part II: Antagonists
Authors: Pratesi P. , Caliendo G. , Silipo C. , Vittoria A.
Published: October 2006

Several sets of ligands acting as antagonists at muscarinic receptor sites are considered by means of QSAR approach. Although the confusing role of the collinearity among vectors associated with physicochemical parameters makes it sometimes difficult to evaluate the quality of structure‐activity correlations, the points discussed in the paper are to draw attention to the development of correlations between biological affinity constants and structural features of antagonists. The results obtained are compared to those relative to an analogous study on the agonists. It is shown that correlation equations are essential for deriving refined concepts on the topology of muscarinic receptor sites.
QSAR: Conceptions and Misconceptions
Authors: Ariëns Everd J.
Published: October 2006

The basis for QSAR‐studies on drugs, pesticides and other xenobiotics is the maxim: “Exposure of nature (including man) and its environment to xenobiotics (including drugs) is only justified if the desirable actions adequately compensate for the undesirable actions and the never fully excluded risks”.

QSAR requires a clearcut congenerity which implies: a 3‐dimensional homology of the various molecular fragments in the chemical framework in the series of compounds “compared”. QSAR in drug etc. development has to comprise activity as well as selectivity. QSAR in relation to drug‐receptor interaction requires restriction to isoregional and isochiral structural variation in the group of congeneric agents compared. In QSAR based on the integral approach, e.g. fractional constants related to lipophilicity or molecular connectivity, overall qualities such as passive membrane penetration and tissue accumulation play a predominant role.

QSMR – Quantitative Structure‐Metabolism Relationship – is an essential factor in in vivo QSAR.

Eudismic analysis is a prerequisite for QSAR dealing with CCD's, CCP's – Composite Chiral Drugs or Pesticides.

Disregard of isomeric ballast invalidates QSAR on chiral agents.
Molecular Modelling Studies on 1,4‐Dihydropyridines Acting at the Ca‐Channel
Authors: Höltje H.‐D.
Published: October 2006

Using molecular modelling techniques, we have compared structural features of a series of 1,4‐dihydropyridine calcium‐channel blockers. Computer graphics modelling suggests that the agonistic as well as the antagonistic behaviour is controlled by substituents at the C‐5 of the DHP‐system, whereas differences in phenyl ring substitution may influence tissue selectivity and negative inotropic activity of the compounds.
University Drug Research: Current State and Future Perspectives
Authors: Mannhold Raimund
Published: October 2006

Current state and future perspectives of university drug research are discussed and compared with the industrial point of view. Synergistic effects of cooperative research between industry and university are considered. Examples of university drug research from our group are given: i.e. determination of drug lipophilicity and optimization of calmodulin ligands.
Generating Optimal Linear PLS Estimations (GOLPE): An Advanced Chemometric Tool for Handling 3D‐QSAR Problems
Authors: Baroni Massimo , Costantino Gabriele , Cruciani Gabriele , Riganelli Daniela , Valigi Roberta , Clementi Sergio
Published: October 2006

An advanced variable selection procedure, called GOLPE, aimed at obtaining PLS regression models with the highest prediction ability is presented and illustrated with an application in 3D‐QSAR. Key steps in the procedure are a preliminary variable selection by means of a D‐optimal design in the loading space, and an iterative evaluation of the effects of individual variables on the model predictivity based on the validation of a number of reduced models, on variables combinations selected according to a FFD strategy.

The procedure is successfully applied to a real 3D‐QSAR case study: the results obtained by GOLPE are compared with those obtained by CoMFA and found to be in good agreement in terms of variable importance, but with a much higher prediction ability. Accordingly, the results encourage to think that it might be used within the CoMFA framework in the place of the present PLS version there, or in CoMFA‐like studies on the structures generated by GRID probes.
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

A 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

Problems 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

The 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

Statistical 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

A 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

The 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

Electron 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

This 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

We 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

Data 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

The 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

Limitations 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

Comparative 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

PLS 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

Quantitative 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

Human 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

Estimation 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

Quantitative 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

Certain 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

We 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

A 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.
Coliphages as alternate indicators of fecal contamination in tropical waters
Authors: Hernández‐Delgado E. A. , Sierra M. L. , Toranzos G. A.
Published: October 2006

Strong evidence has recently been found against the use of fecal coliforms as indicator organisms of fecal contamination in tropical waters due to their indigenous nature in pristine waters. There is a great need for the development of more rapid, accurate, and low‐cost techniques for determining bacteriological water quality. Coliphages seem to be an excellent alternative. We have developed a method to analyze large volumes of pristine water, which we compared to a commonly used direct method. It involves the filtration of water through positively charged filters and a virus‐elution step. The eluent is then mixed with culture medium, a host bacterium, and incubated. We sampled pristine tropical rivers, water collected from bromeliads (epiphytic vegetation), sewage‐contaminated waters, and marine waters. Concentrations of indicator bacteria were higher than recommended levels for recreational waters, including bromeliad waters. Indicators levels were higher in bromeliad waters than in sewage‐contaminated rivers. Phages were isolated only from waters being used for recreational purposes and from sites known to be contaminated with domestic sewage, but not from pristine or bromeliad waters. These results suggest that there is a correlation between the presence of coliphages and fecal contamination. This further suggests that coliphages may be reliable indicators of fecal contamination in the environment.
Shellfish and marine water microbiological quality
Authors: Sato M. I. Z. , Monteiro C. K. , Stoppe N. C. , Sanchez P. S. , Ostini S. , Matté G. R.
Published: October 2006

Sewage discharge to the marine environment constitutes an important problem faced by public health and environmental managers, and exerts great economic and social impact on shellfish‐producing areas. This study aims at characterizing the water quality and shellfish sanitary conditions of different growing areas on the northern coast of the São Paulo State. Seventy‐two samples of water and shellfish were enumerated for total and fecal coliforms, and were analyzed for the presence ofSalmonella. The most probable number ofVibrio parahaemolyticuswas also determined for shellfish samples. Shellfish contamination was directly related to the bacteriological pollution of the water, such that in growing areas not contaminated with sewage discharges, 100% of shellfish samples presented themselves as being safe to be consumed.Salmonellawas absent in all samples analyzed andV. parahaemolyticuswas present in lower densities in shellfish samples. The percentage of water samples that did not comply to the standard were much higher than those of shellfish samples, indicating the need to reevaluate the permitted values of the Brazilian legislation both for shellfish “in natura” and for growing waters. This study also establishes the need for a better management of shellfish‐producing areas, especially those more polluted, in parallel with the development of a Brazilian Shellfish Sanitation Program, in order to protect the quality of these organisms and consequently human health.