bluuebunny/crossref_metadata_2025 huggingface dataset:
High resolution gas chromatography analysis of ‘espinheira santa’ (Maytenus ilicifolia and M. aquifolium): Analysis of crude drug adulterations
Authors: Vilegas Janete H. Y. , Lanças Fernando M. , Cervi Armando C.
Published: October 2006

High resolution gas chromatographic analysis of reference samples of ‘espinheira santa’ (Maytenus ilicifolia and M. aquifolium, Celastraceae) and of samples purchased in Brazilian herbal medicine stores showed that friedelan‐3‐ol and friedelin can be utilized as markers for the identification of ‘espinheira santa’ and for the recognition of authentic and adulterated samples in a fast and simple procedure.
The low calorie natural sweetener stevioside: Nephrotoxicity and its relationship to urinary enzyme excretion in the rat
Authors: Toskulkao Chaivat , Deechakawan Wimon , Leardkamolkarn Vijittra , Glinsukon Thirayudh , Buddhasukh Dhuang
Published: October 2006

The relationships between urinary enzyme levels and changes in blood urea nitrogen (BUN) and plasma creatinine levels, along with simultaneous ultrastructural changes of the kidney, were studied in rats treated with stevioside. BUN levels increased at 3 h onward after subcutaneous injection (s.c.) with stevioside (1.5 g/kg BW). The maximum increases in BUN and creatinine were approximately 180% and 132% at 9 h after stevioside injection, respectively. At this time, stevioside also caused significant increases in glucosuria, alkaline phosphatase (AP) and γ‐glutamyl transpeptidase (γ‐GTP) but no significant changes in proteinuria, N‐acetyl‐β‐D‐glucuronidase (NAG) or glutathione‐S‐transferase (GSH‐S‐TF). Histopathological examination of the kidney induced by stevioside revealed degeneration of the proximal convoluted tubule cells but no relation to lipid peroxide formation was detected. These results suggest that stevioside induced nephrotoxicity at the proximal convoluted tubules rather than at the glomeruli and other tubules presumably by a defect of cell volume regulation due to depletion of intracellular ATP and disruption of microvilli, and nuclear dysfunction.
Inhibition of tumour promotion and cell proliferation by plant polyphenols
Authors: Ramanathan R. , Das N. P. , Tan C. H.
Published: October 2006

The plant polyphenols: 2‐hydroxy chalcone, quercetin and tannic acid exhibited varying antiproliferative effects on two mouse cell lines—NIH 3T3 and L929. Whilst 2‐hydroxy chalcone and tannic acid (at 250 μM concentration) were able to exert 90% and 56% growth inhibition, respectively, quercetin at the same concentration had no effect on NIH 3T3 cells. However, these test compounds could exert significant growth inhibition on L929 cells at a concentration as low as 50 μM. At the highest concentration tested (250 μM), 2‐hydroxy chalcone, quercetin and tannic acid showed 87%, 61% and 78% growth inhibition, respectively. The observed difference in potencies of the test compounds for the two cell lines indicated that their actions are cell line specific. When tested in vivo on mice, the order of potency of the test compounds in inhibiting benzo[a]pyrene‐induced mouse skin carcinogenesis was tannic acid > 2‐hydroxy chalcone > quercetin. No correlation was observed between the efficacy of the test compounds and lipid peroxidation in vivo.
A practical, reproducible measure of murine anaphylaxis: Blood pressure monitoring of anaphylaxis and effect of Impatiens balsamina
Authors: Ishiguro Kyoko , Fukumoto Hisae , Osada Shiho , Isoi Koichiro , Semma Masanori
Published: October 2006

Monitoring blood pressure (BP) was found to be a reliable and effective method for studying anaphylactic responses of mice not subjected to fatal shock. This method has the additional merit of allowing use of the experimental animals for long‐term allergy research. Using this system, we estimated the antianaphylactic effects of a 35% ethanol extract (IB) of petals of Impatiens balsamina L.
Effect of the water extract of Galega officinalis L. on human platelet aggregation in vitro
Authors: Atanasov Atanas Todorov
Published: October 2006

Galega officinalis L. is a traditional medicinal plant from Bulgaria. It was found that the aqueous extract of Herba Galegae suppressed platelet aggregation in vitro induced by adenosine diphosphate, epinephrine, thrombin and collagen. The compounds with antiaggregating action have not as yet been isolated from Galega officinalis.
Hypoglycaemic activity of Geranium core‐core, Oxalis rosea and Plantago major extract in rats
Authors: Rodriguez J. , Loyola J. I. , Maulén G. , Schmeda‐Hirschmann G.
Published: October 2006

The hypoglycaemic activity of ‘Core‐core’ (Geranium core‐core, Geraniaceae), ‘Culle’ (Oxalis rosea, Oxalidaceae) and ‘Llantén’ (Plantago major, Plantaginaceae) crude extracts was assessed in normoglycaemic rats. Furthermore, the hypoglycaemic activity of Core‐core extract was evaluated in alloxan‐diabetic rats. A single oral dose of 500 mg/kg Core‐core extract significantly reduced glycaemia in normal rats under glucose tolerance test conditions (p < 0.01), while Culle and Llantén were devoid of activity. The effect was lower than a single oral dose of 100 mg/kg tolbutamide. After 7 days oral treatment at 250 mg extract/kg body weight, Core‐core significantly reduced glycaemia (p<0.01) in normal rats under oral glucose tolerance conditions. In alloxan‐diabetic rats, a single oral dose of 500 mg/kg and chronic treatment at 250 mg/kg Core‐core extract significantly reduced glycaemia in glucose tolerance test conditions at p < 0.05 and p < 0.01, respectively. During the acute oral toxicity study, animals treated with Core‐core extract exhibited no symptoms of drug‐induced toxicity with doses up to 5 g/kg.
Enhancement of in vitro nonspecific immune functions by African plant extracts
Authors: Ottendorfer D. , Frevert J. , Kaufmann R. , Beuscher N. , Bodinet C. , Msonthi J. D. , Marston A. , Hostettmann K.
Published: October 2006

The in vitro immunomodulatory activities of extracts from African medicinal plants have been studied. Certain extracts exerted enhancing effects in a concentration dependent manner on immune cells from three different strains of mice. Among these were an enhancement of phagocytic activity of peritoneal macrophages and tumoricidal potential of macrophages, and stimulation of the oxidative burst of macrophages and granulocytes. In contrast, the proliferative capacity of lymphocytes was only marginally affected. Enhanced macrophage and granulocyte activation was also detected using leucocytes of the LPS nonresponder strain C3H/HeJ. From the latter it can be concluded that the observed stimulatory effects of the plant extracts in vitro were not due to contamination with lipopolysaccharides.
Antithrombotic activity of ternatin, a tetramethoxy flavone from Egletes viscosa less
Authors: Souza M. F. , Cunha G. M. A. , Fontenele J. B. , Viana G. S. B. , Rao V. S. N. , Silveira E. R.
Published: October 2006

Ternatin, a tetramethoxy flavone isolated from Egletes viscosa Less. was evaluated for a possible antithrombotic acitivity on in vitro platelet aggregation induced by ADP and in vivo mouse model of tail thrombosis induced by kappa‐carrageenan (KC). ADP‐induced platelet aggegation was inhibited by ternatin in a concentration‐dependent manner with an IC50 of 390 μM. It also provided marked protection of mice from thrombotic challenge with KC. Tail thrombosis was totally prevented in mice that received ternatin prophylactically (1 h prior to KC injection) whereas therapeutically (4 h after KC injection) administered ternatin effectively reduced the length of the thrombosed/infarcted part of the tail. The observations suggest an antithrombotic action of ternatin.
β‐glucuronidase inhibition and diuretic activity of Fabiana imbricata R. & P. (Solanaceae)
Authors: Schmeda‐Hirschmann G. , Loyola J. I. , Reyes S. , Hubert E. , Rodriguez M. , Rodriguez J. , Dutra‐Behrens M.
Published: October 2006

The hydroalcoholic extract of Fabiana imbricata inhibited the enzyme β‐glucuronidase (β‐gluc) in vitro. Bioassay‐guided isolation led to scopoletin as the main active constituent of F. imbricata. Scopoletin was a noncompetitive inhibitor of β‐D‐glucuronidase with a Ki value of 4 × 10−5 M. A single oral dose of 250 mg/kg body weight F. imbricata extract produced a significant increase (p<0.05) in the urine output of rats. The diuretic effect of the extract was weak in comparison with hydrochlorothiazide at 25 mg/kg. In the acute oral toxicity study in rats, ‘Pichi’ was shown to be a low toxicity crude drug at doses up to 5 g crude extract/kg body weight. At concentrations up to 0.50 mg/mL, the crude extract did not increase the number of chromosome aberrations in the in vitro human lymphocyte assay.
Confirmation that tannin‐containing crude drugs have a uraemic toxin‐decreasing action
Authors: Yokozawa Takako , Fujioka Koji , Oura Hikokichi , Tanaka Takashi , Nonaka Gen‐Ichiro , Nishioka Itsuo
Published: October 2006

Nine crude drugs containing tannins were selected in order to examine their actions on rats with renal failure. The levels of urea nitrogen, creatinine (Cr), methylguanidine (MG) and guanidinosuccinic acid (GSA) were decreased markedly and significantly in rats given Ephedrae Herba. Chebulae Fructus and Geranii Herba produced the same effect on uraemic toxins as that of Ephedrae Herba. MG was significantly decreased by all tannin‐containing crude drugs. However, there were no particular changes in these parameters after administration of non‐tannin‐containing crude drugs. The levels of urea nitrogen, Cr, MG and GSA showed a tendency to be increased in rats given Rehmanniae Radix, Coptidis Rhizoma, Scutellariae Radix and Alismatis Rhizoma, but MG was decreased significantly in rats given Bupleuri Radix. Non‐tannin compounds also produced no significant decreases in the levels of uraemic toxins.
Reversal of efflux‐mediated tetracycline resistance in Staphylococcus aureus clinical isolates by Ginseng prosapogenins
Authors: Hasegawa Hideo , Matsumiya Satoshi , Uchiyama Masamori , Inouye Yoshio , Kasai Ryoji , Yamasaki Kazuo
Published: October 2006

A pair of tetracycline‐resistant Staphylococcus aureus strains carrying different resistance determinants, tetK and tetM, were employed to screen some ginseng prosapogenins as antagonists of tetracycline resistance. The tetK gene encodes TetK efflux pump and the tetM gene define a ribosomal‐level resistance. The susceptibility of two strains to tetracycline was measured in parallel in the presence of various concentrations of test compounds. The efflux pump not ribosomal protection was adversely affected by ginsenosides Rh2, F1, 20‐O‐β‐D‐glucopyranosyl‐20(S)‐dammar‐3, 20‐diol (compound K), 20(R)‐ginsenoside Rh2 and their aglycones at nontoxic concentrations, reversing tetracycline resistance in the tetK‐carrying S. aureus.
Effect of picroliv on antioxidant‐system in liver of rats, after partial hepatectomy
Authors: Rastogi Ravi , Saksena Seema , Garg N. K. , Dhawan B. N.
Published: October 2006

Levels of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase in the serum of rats increased maximally at 12 h and bilirubin at 24 h, while total proteins decreased maximally at 48 h after partial hepatectomy. The levels of total lipids, reduced glutathione, glutathione peroxidase and glutathione reductase in liver increased maximally at 12 h and catalase at 24 h, but the activities of peroxidase, glutathione‐S‐transferase and superoxide dismutase decreased maximally at 12 h. After the period of maximal initial increase/decrease, the changes in these parameters in liver and serum started recovering towards their prehepatectomy levels. When a similar study was performed in rats fed 12 mg/kg body wt picroliv (an iridoid glycoside fraction of Picrorhiza kurroa) once daily for 7 days, the rate of recovery of glutamate oxaloacetate transaminase, glutamate pyruvate transaminase and alkaline phosphatase in serum and total lipids, reduced glutathione, peroxidase, catalase and glutathione‐S‐transferase in liver was faster.
Polypeptides of Aloe barbadensis miller
Authors: Winters Wendell D. , Bouthet Catherine
Published: October 2006

Major polypeptide species of proteins have been identified and analysed by sodium dodecyl sulphate polyacrylamide gel electrophoresis in fresh extracts of the whole leaf, leaf gel, root and stalk portions of Aloe barbadensis Miller plants of immature, young and mature ages. Extracts of the fresh Aloe plant portions were prepared by dissection, tissue disruption, differential centrifugation and gel filtration methods. Extracted plant portions analysed by separation electrophoresis were also assayed by biochemical and immunological techniques for the presence of lectin associated reactions, i.e. agglutination or mitogenicity. Results of the separation electrophoresis analysis of extracts prepared from fresh whole leaves and leaf gel of mature Aloe barbadensis Miller plants revealed 23 identifiable different polypeptides. Molecular weights of these polypeptides, calculated from sets of molecular weight reference standards, ranged from 70 000 for the largest to 3000 for the smallest. Electrophoresis profiles of commercially processed and freshly processed Aloe barbadensis Miller and Aloe saponaria Haw leaf gel extracts revealed similar patterns for major peptides. Treatment of mature whole Aloe leaf extracts with acidic and alkaline conditions revealed distinct changes in pH stability of ten peptides. Comparisons of separation electrophoresis profiles of fresh extracts of Aloe whole leaves and of leaf gel portions revealed marked differences in both molecular weights and concentrations of peptides found in extracts from mature, young or immature plants. This report is the first to describe the nature and types of polypeptides detected in extracts of whole leaf, leaf gel, stalk and root portions of immature, young and mature Aloe plants. Accordingly, information in this report may be of considerable value in helping to identify and characterize Aloe substances present during processing in extracts and in products.
Activation of lucidin‐3‐O‐primveroside mutagenicity by hesperidinase
Authors: Chulasiri Malyn , Matsushima Taijiro , Yoshihira Kunitoshi
Published: October 2006

At the maximum dose tested, 100 μg/plate, lucidin‐3‐O‐primveroside (LUC‐Prv) exhibited mutagenic potential in Salmonella typhimurium TA100 without S9 mix but not with the addition of this preparation. When the pH of the tested system was reduced from 7.4 to 6.5, the same results were obtained. However, after hesperidinase treatment at pH 6.5, higher mutagenicity was demonstrated, and the mutagenicity of the hydrolysis product in TA100 decreased in the presence of S9 mix. When the preincubation time of the mixture was kept longer, i.e. 30, 60 and 120 min, the number of revertants in TA100 without S9 mix became higher. When the concentration of hesperidinase was varied from 5 × 10−5 to 2.5 × 10−2 unit, no change in the number of revertants was observed. In contrast, LUC‐Prv and its hydrolysis products demonstrated no mutagenicity in TA98 by the same tested system.
Hypotensive action of syringin from Syringa vulgaris
Authors: Ahmad Mansoor , Aftab Khalid
Published: October 2006

Naturally occurring syringin was isolated from the bark of Syringa vulgaris (Oleaceae), and its pharmacological action examined on anaesthetized Wistar rats. When the drug was introduced intravenously, it caused a dose dependent fall in systolic, diastolic and mean arterial blood pressure, whereas heart rate also decreased at a slightly higher dose. The hypotensive activity was not inhibited by antihistamine or antimuscarinic agents. Syringin has no effect on the pressor effect induced by norepinephrine or carotid occlusion.
Pharmacological screening of the methanol and dichloromethanol extracts of Genista patens
Authors: Bello R. , Barrachina M. D. , Martínez‐Cuesta M. A. , Esplugues J. , Yúfera E. Primo
Published: October 2006

The pharmacological effects of the dichloromethanol and methanol extracts obtained from leaves and stems of Genista patens DC were analysed in in vitro and in vivo models. Both extracts showed low acute toxicity (LD50 > 3 g/kg), CNS depressor and antiinflammatory activity, and similar analgesic effect in models of chemical and thermal stimulation. Furthermore, the dichloromethanol extract (1–20 mg/kg) induced a pronounced dose‐dependent decrease on blood pressure. On isolated organs, the dichloromethanol extract (1, 10, 100 μg/mL) shifted the concentration‐effect curve to the right for ACh and reduced the Emax induced by histamine without modifying responses induced by noradrenaline and serotonin.
Activity of Osyris quadripartita salzm. Methanol extract on capillary permeability in rats
Authors: Gómez M. E. , Ayuso M. J. , Toro M. V.
Published: October 2006

A methanol extract of Osyris quadripartita Salzm., with high content of flavonoids was found to be effective in reducing the increased capillary permeability induced in rats by various chemical mediators involved in the inflammatory process, namely histamine (HA), 5‐hydroxy‐triptamine (5‐HT) and bradykinin (BK). Pretreatment with the MeOH extract (250 mg/kg i.p.) afforded significant protection against the increase in capillary permeability induced by HA (% protection = 96.6), 5‐HT (% protection = 53.8) and BK (% protection = 87.9).
Modulatory effects of Artemisia annua extracts on human complement, neutrophil oxidative burst and proliferation of T lymphocytes
Authors: Kroes B. H. , van Ufford H. C. Quarles , Boer R. L. Tinbergen‐de , van den Berg A. J. J. , Beukelman C. J. , Labadie R. P. , van Dijk H.
Published: October 2006

Air‐dried aerial parts of Artemisia annua were extracted with petroleum ether, diethyl ether, ethyl acetate, ethanol and water successively. The extracts were screened for their in vitro effects on human complement, proliferation of T lymphocytes, and chemiluminescence by zymosan‐stimulated polymorphonuclear leukocytes. All extracts exhibited dose‐dependent inhibitory activities in our immunoassays. The highest activity towards the classical pathway of complement was found in ethyl acetate and ethanol extracts, whereas in the chemiluminescence assay, diethyl ether and ethyl acetate extracts showed the most pronounced inhibitory activities. In the T‐cell proliferation assay, the diethyl ether extract exhibited the most potent inhibitory effect. Artemisinin showed no immunomodulatory activity in our assays.
13C‐NMR and 1H‐NMR Chemical Shifts in a Correlation Analysis of Benzotriazole Derivatives Active as Plant Growth Regulators
Authors: Sparatore F. , Caliendo G. , La Rotonda M. I. , Novellino E. , Silipo C. , Vittoria A.
Published: October 2006

Following preliminary observations on auxin‐like activity of several 1‐ and 2‐substituted benzotriazole isomers, a few new derivatives have been synthesized and tested. In attempting to quantify by QSAR the structural properties of a large set of compounds and with the aim to rationalize the structure‐activity relationships taken into account in a previous study by a set of indicator variables, attention was turned to the analysis of 13C‐NMR and 1H‐NMR chemical shifts relative to the substituent carbon atom attached on the nitrogen of the benzotriazole ring. The 13C‐NMR chemical shift can be useful as an independent parameter in QSAR. Considerations of the general applicability of sigma inductive constants for predicting physicochemical properties of complex heteroaromatic systems such as those under study are discussed. Finally it is shown that there are important electronic and steric components which play a major role in promoting the auxin‐like activity of compounds under examination.
Modeling the Interaction of Small Organic Molecules with Biomacromolecules (the Oasis Approach). V. Toxicity of Phenols to Algae “Lemna Minor”
Authors: Mekenyan Ovanes G. , Bonchev Danail G. , Enchev Venelin G.
Published: October 2006

The recently developed OASIS approach

See Refs. 1 to 4 for Parts I to IV of this series, as well as Refs. 6 and 7 for a detailed description of the approach.

is applied to the modeling of substituted phenol toxicity. The best models derived show a certain contribution of the electronic factor in addition to the hydrophobicity factor; while the phenol geometric properties were found to be insignificant. The superdelocalizability indices characterizing the electron acceptor properties of the oxygen and its neighbouring carbon atom were found to be of importance along with the phenol acidity used in previous models and they can replace the latter in calculating substituted phenol toxicities. The complicated mechanism of the toxic agent‐receptor interaction is thus supposed to include some charge transfer from the biosubstrate to these two phenolic atoms with possible formation of a covalent or a hydrogen bond, although the charge‐controlled reactions seem to prevail.
Calculation of Molecular Volumes from Molecular Fragments via Valence Electron Indices
Authors: Govers Harrie , De Voogt Pim
Published: October 2006

It is shown that van der Waals volumes of 1‐atomic fragments, c.q. hydrides, can be predicted accurately via indices denoting the number of non‐hydrogen valence electrons. The introduction of a principal quantum number dependence of orbital volumes turned out to be necessary, which led to a modified molecular connectivity model. From these fragmental indices molecular valence electron indices were derived, which are demonstrated to be accurate predictors of the molecular volume of polycyclic aromatic compounds in an additive model.
Substructural Analysis of Antineoplastic Compounds in Respect of in Vivo Tumor Models
Authors: Pajeva Ilza , Golovinsky Evgeny
Published: October 2006

A substructural analysis of antineoplastic compounds is provided with respect to two in vivo tumor models: lymphoid leukemia L1210 (L1210) and Lewis lung carcinoma (LL). The activity data are expressed by 4 levels of activity against L1210 and LL. The structures of the compounds are described by means of structural features derived from a structure‐activity relationship (SAR) oriented language for two‐dimensional chemical structure representation. A statistical‐heuristic technique is applied to obtain, for each structural feature, a weight for each activity level. On the basis of the weights, the contributions of the structural features to the probabilities of activity against L1210 and LL models are estimated. The features contributing to the relevant probabilities to the greatest extent are located and analyzed from a biochemical point of view. The results obtained show the suitability of the features for compounds' activity recognition and identification of substructures significant for the investigated activities.
QSAR Analysis in 2,4‐Diamino‐6,7‐dimethoxy Quinoline Derivatives – α1‐Adrenoceptor Antagonists – Using the Partial Least Squares (PLS) Method and Theoretical Molecular Descriptors
Authors: Cocchi Marina , Menziani M. Cristina , Rastelli Giulio , de Benedetti Pier G.
Published: October 2006

Theoretical molecular descriptors were derived for fifteen 2,4‐diamino‐6,7‐dimethoxy quinoline derivatives α1‐adrenoceptor antagonists both from molecular orbital indices (AM1) and modelling of molecular shape (QUANTA 2.1.A). Quantitative structure‐activity relationships (QSAR) were obtained between the theoretical descriptors and the α1‐binding affinities (from literature) by using the Partial Least squares (PLS) method. The QSAR model obtained is satisfying both from a predictive and interpretative point of view and clearly depicts the role of the protonated quinoline nucleus at the α1‐adrenoceptor. In fact, the more electrophilic the N1‐H (+) group, the higher the α1‐binding affinity. Furthermore, it suggests that hydrophobicity is a second key feature for an effective receptor interaction.
The Reactivity of 2‐(4‐Phenylsubstituted)‐α,β‐Unsaturated Carboxylic Acids with Diazodiphenylmethane
Authors: Ušćaumlića Gordana S. , Krstića Vera V. , Muškatirovića Milan D.
Published: October 2006

In connection with a study of the transmission of polar effects through ring double bonds, double bonds in open chain systems and delocalized double bonds, the reactivity of 2‐(4‐phenylsubstituted)‐α,β‐unsaturated carboxylic acids with diazodiphenylmethane in ethanol was investigated. The rate data for 2‐(4‐phenylsubstituted)‐cyclohex‐1‐ene carboxylic acids, 2‐(4‐phenylsubstituted)‐benzene carboxylic acids, cis‐3‐and 4‐substituted and trans‐3‐ and 4‐substituted cinnamic acids were correlated with a simple Hammett equation by means of the σp and σm constants and with an extended Hammett equation to detect the presence or absence of steric effects as well as the composition of the electrical effect. The transmission of polar effects through the different double bonds was discussed in terms of the polar susceptibility constant δ and steric interaction of the phenyl and carboxylic group.
Inhibition of Thermolysin and Bacillus brevis Neutral Proteinase by Organic Solvents and Some Related Compounds
Authors: Paberit Nadezhda , Paberit Mart
Published: October 2006

Inhibition of thermolysin and Bacillus brevis neutral proteinase (NP) reactions with N‐(3‐(2′‐furyl)acryloyl)glycyl‐L‐leucinamide by organic solvents and some other simple organic compounds (alkanols, aromatic compounds etc., in total 33 substances) was studied. The enzymes showed very similar affinities for the inhibitors in the whole range of Ki variation (3.7 orders of magnitude). A linear dependence with a nearly unitary slope between the pKi values and log P's of the compounds was found. The inhibitory power of the compounds, whose molecules are longer than those of propanol or benzene, depended on their ability to donate a hydrogen bond. pKi's of the compounds, in which substituents attached to the propyl group or benzene ring are unable to donate the hydrogen bond, fell off the correlation line; the deviation was proportional to the van der Waals volume of the substituent. pKi's of tert‐butanol and cyclohexanol also fell off the correlation line. Geometrical thickness of their molecules exceeds that of the other studied inhibitors; this may explain their lowered affinity for the enzymes. 6,6‐ or 7,5‐bicyclic compounds did not inhibit these enzymes.
Application of Functional‐Link Net in QSAR. 1. QSAR for Activity Data Given by Continuous Variate
Authors: Liu Qian , Hirono Shuichi , Moriguchi Ikuo
Published: October 2006

We attempted to apply a new pattern recognition method called “functional‐link net” (Klassen and Pao, 1988) to QSAR. In contrast to the linear weighting produced by the generalized delta rule net often used in neural nets, the functional‐link net acts on a pattern element (a structural parameter in QSAR) or on the entire pattern itself to generate a set of nonlinear functions. In usual QSAR studies, linear forms of parameters are generally used. But, in many cases, parameters might contribute semilinearly to activity. Such a semilinear contribution of parameters can be examined by semilinearly transforming the parameters into a new parameter vector using a procedure with the architecture of the functional‐link net. The new method presented here was devised for analysis of QSAR from activity data given by a continuous variate. The application of this method to QSAR of several data sets of carboquon analogues with antileukemic activity gave better results than those given by multiple regression analysis of the same data sets. The comparison of the results with those given by the generalized delta rule net also showed that FUNCLINK was superior in the predictive ability.
A Study on pK and Partition Coefficient of Substituted Benzoic Acids in SDS Anionic Micellar System
Authors: Garrone Adele , Marengo Emilio , Fornatto Elisa , Gasco Alberto
Published: October 2006

Apparent ionization constants (pK) of a series of m‐ and p‐ substituted benzoic acids were measured by potentiometric titrations in an anionic micellar system (SDS, Sodium Dodecyl Sulphate). From these data, the binding constant K and the partition coefficient between micellar and aqueous pseudophases Pmic, were estimated for each derivative. Collander type regressions between log Pmic and log Poct are discussed. pK values correlate well with a linear combination of σ, πoct and MR molecular descriptors.
Routes to Histamine H2‐Agonists
Authors: Timmerman Hendrik
Published: October 2006

In this paper the design, synthesis and primary biological testing of several new H2‐agonists are presented. The existing agonists dimaprit and impromidine have been used as starting points.

Dimaprit seems to be the only member of its class which is an H2‐agonist; close analogues of dimaprit proved to be inactive as H2‐agonists.

In impromidine the moieties constituting the molecule are considered to play different roles: the unsubstituted imidazole is required for receptor activation, whereas the guanidino and the methyl‐substituted imidazole are needed for additional receptor binding. Based on this concept several new and potent impromidine‐like H2‐agonists were obtained.

Using the fastidious nature of dimaprit for H2‐agonism, computational approaches lead to the design of 2‐aminothiazoles as H2‐agonists. Several new H2‐agonists, also of the impromidine‐type, were obtained. This class of compounds provides not only potent, but also selective (negligible effects on H1‐ and H3‐receptors) H2‐agonists.
Industrial Drug Research: Development of Ca‐Antagonistic Vasodilators
Authors: Edgar Boo
Published: October 2006

The prime aim of industrial drug research is the development of new therapeutics; correspondingly it has to consider not only drug‐receptor interaction, but also such important aspects as pharmacokinetics, side effects and toxicology. An example for this complex pattern of industrial drug research is given here for the development of the dihydropyridine‐like Ca‐antagonist felodipine. Several felodipine analogues with different ester groups in 3‐ and 5‐position of the dihydropyridine ring were synthesized and their biological activities evaluated in screening procedures. Both in vitro and in vivo potency was determined, as well as selectivity for vascular smooth muscle, in comparison to cardiac muscle. Structure‐activity relationships were studied in a group of these dihydropyridine esters (DHP‐esters) to ensure that the compound selected for further biological evaluation (felodipine) is close to the optimum as far as the screening parameters are concerned.

In the second part of the paper pharmacokinetic properties and clinical profile of felodipine are summarized.
Amino Acids Characterization by GRID and Multivariate Data Analysis
Authors: Cocchi Marina , Johansson Erik
Published: October 2006

The twenty coded amino acids have been characterized by their interaction energies, calculated by the program GRID, with six different probes mimicking various functional groups which can be involved in peptide‐peptide interactions. Principal Component Analysis (PCA) have been used to derive amino acids principal properties and comparing the amino acids classification obtained with the one derived by the previous published amino acids z‐scales. Partial Least Squares (PLS) method has been used to test the performance of GRID probe interaction energies and the newly derived principal properties in peptide's QSAR modeling. A better separation of amino acids according to the electronic features of the side chain is obtained. The inhibitory activity of the set of peptides considered has been satisfactorally modelled.
“Classical” and “Magnetic” Aromaticities as new Descriptors for Heteroaromatics in QSAR. Part 3 [1]. Principal Properties for Heteroaromatics
Authors: Caruso Loredana , Musumarra Giuseppe , Katritzky Alan R.
Published: October 2006

A set of twentyfour monocyclic and benzo‐fused heteroaromatics were multivariately characterized by five experimental aromaticity descriptors: one geometric, two energetic and two magnetic aromaticity scales. Two principal properties (PP), designated as “classical” and “magnetic” respectively, were calculated from the 5 × 24 data set, by a two principal components (PC) model explaining 79.5% of variance. The first PP was shown to be related to I'x aromaticity scale, available for a wider set of heteroaromatics. The above PPs, together with other descriptors accounting for the position of attachment of the ring, may be used in developing strategies for selecting heteroaromatic moieties in experimental design aimed at the optimization of structures for pharmaceutical or toxicological testing.
On the Reliability of Calculated Log P‐values: Rekker, Hansch/Leo and Suzuki Approach
Authors: Rekker R. F. , Laak A. M. Ter , Mannhold R.
Published: October 2006

A number of fragmental approaches for calculation of drug lipophilicity (log P) have been developed in recent years.

Among these the procedures of Rekker, Hansch and Leo and that of Suzuki and Kudo offer good possibilities for setting up computerized versions of log‐P calculation. This paper presents a comparative overview of the results of these three approaches for two series of hydrocarbon structures as well as for 36 selected drugs as tabulated by Rekker and Mannhold in their monograph “Calculation of Drug Lipophilicity”.

The presented data demonstrate quite clearly that in a number of cases unexpected and unacceptable artefacts show up. Our final conclusion is that – at least for the series we chose for demonstration – the ultimate goal for faultless log P‐calculations, although within reach, has not yet been fully realized.
Comparison of QSAR and Molecular Similarity Approaches for a Structure‐Activity Relationship Study of DHFR Inhibitors. DHFR Inhibitors: QSAR and Molecular Similarity Approaches
Authors: Stanton David T. , Murray Wallace J. , Jurs Peter C.
Published: October 2006

A comparison is made between classical QSAR approaches using multivariate linear regression analysis and molecular similarity analysis (MSA) using inhibitors of dihydrofolate reductase (DHFR). A wide variety of descriptors derived directly from molecular structure are examined with both QSAR and MSA approaches. Three separate measures of molecular similarity are examined to determine how each compares with the QSAR method in the context of the descriptors used. The QSAR method yielded a model with a R2 = 0.927 whose descriptors indicate that molecular size, shape and hydrogen bonding acceptor groups are important to activity. Molecular similarity approaches did not provide as good a model. The best correlation between pKi values and any given similarity metric was obtained with the Tanimoto coefficient.
Relationship Between the Lipophilicity and Specific Hydrophobic Surface Area of Non Homologous Series of Nonionic Surfactants
Authors: Forgács Esther , Cserháti Tibor
Published: October 2006

The lipophilicity (RM), specific hydrophobic surface area and the relative strength of interaction between trimethyl‐β‐cyclodextrin and 39 nonionic surfactants having different hydrophobic moieties has been determined by charge‐transfer thin‐layer chromatography using methanol as an organic modifier. RM values decreased linearly with increasing concentration of methanol. The significant correlation between the RM value extrapolated to water and the specific hydrophobic surface area indicates that these surfactants can be considered from the chromatographic point of view as a homologous series of solutes independently of their structural inhomogeneity. Stepwise regression analysis suggested that the length of alkyl chain in the hydrophobic moiety, the presence of sorbite and phenyl group in the surfactant molecule, and the number of ethyleneoxide groups per molecule have the highest impact on their hydrophobic parameters. The relative strength of surfactant‐cyclodextrin interaction significantly depended on the lipophilicity of the surfactants, and on the presence of phenyl group and ester bonds in the surfactant molecule.
A Three‐Dimensional Technique for the Calculation of Octanol‐Water Partition Coefficients
Authors: Waller Chris L.
Published: October 2006

Octanol‐water partition coefficients, as logPs, are frequently used to describe transportability and membrane permeability of chemical compounds. Because of this they represent an integral part of quantitative structure‐activity relationship (QSAR) theory. Since the analytical determination of logPs is a tedious process, many empirical techniques for their calculation have been developed. The additive fragment‐based technique, clogP, represents the most highly validated algorithm designed for this purpose. However, it has been observed that clogP is incapable of distinguishing between structural isomers in a congeneric series of compounds. This is primarily a result of the lack of necessary “factors” for the characterization of the substituent effects. As an alternative to additional parameterization of the clogP methodology, a novel technique for the calculation of octanol‐water partition coefficients based on three‐dimensional descriptors was developed which is capable of accurately predicting the experimentally‐determined logPs for a congeneric series of structural isomers.
Theoretical Descriptors of Nucleic Acid Bases. Application to DNA Promoter Sequences
Authors: Norinder Ulf , Jonsson Jörgen
Published: October 2006

Theoretical descriptors for nucleic acids are generated by applying principal component analysis to 3‐D field data of non‐bonded and charge‐charge interaction type. These descriptors are subsequently used to develop quantitative sequence‐property models with good predictability for E. coli transcriptional DNA‐promoter sequences using the method of partial least squares projections to latent structures (PLS). The resulting 3‐D contour maps can be used to investigate requirements for new nucleic acids to be synthesized in order to obtain sequences with altered activities.
Theoretical Investigations on Antimuscarinic Ethylthio and Ethoxy Derivatives of Adiphenine and 4‐DAMP
Authors: Romanelli M. Novella , Höltje Hans‐Dieter , Scapecchi Serena
Published: October 2006

The unexpected differences in biological activity of some sulfurated muscarinic antagonists, compared to their oxygenated analogues, is explained using theoretical methods based on molecular mechanics and molecular orbital calculations. Interaction energies calculated for both types of ligands with a receptor model (M1) show that binding is more favourable for the sulfurated than the oxygenated molecules. This can be explained with the different geometrical and electronical properties (but not conformational) of the molecules.
Comparative Molecular Field Analysis of Compounds with CYP2A5 Binding Affinity
Authors: Poso Antti , Juvonen Risto , Gynther Jukka
Published: October 2006

Sixteen planar coumarin type substrates and inhibitors of cyto‐chrome P4502A5 (CYP2A5) were analyzed using the Comparative Molecular Field Analysis (CoMFA) method [1]. The analysis was carried out using traditional steric and electrostatic fields, the energy of the lowest unoccupied molecular orbital (LUMO) and the highest occupied molecular orbital (HOMO), dipole moment and LUMO as a 3‐D field (square of the wave function). The highest cross‐validated r2‐value (q2), 0.741, was obtained (five PLS components) when steric and electrostatic fields were used together. However, when LUMO field or energy was included in the analyses, q2‐values decreased (0.723 and 0.724, respectively) and the required number of PLS components also decreased to three. In this case the LUMO field most probably reflects structural information not shown in traditional fields. CoMFA contour maps emphasized the importance of the ligands' lactone structure, together with the methoxy group of methoxsalen, for high CYP2A5 binding affinity.
Structural Requirements of the Binding of Nonionic Surfactants to Sodium Dodecylsulfate
Authors: Forgács Esther , Cserhäti Tibor
Published: October 2006

The interaction of 24 nonionic surfactants (6 ethoxylated stearic acid derivatives, 10 ethoxylated fatty alcohols, and 8 ethoxylated anhydrosorbite derivatives) with the anionic surfactant sodium dodecylsulfate (SDS) was studied by reversed‐phase chromatography, and the relative strength of interaction has been calculated. Principal component analysis (PCA) was used for the determination of molecular substructures and physicochemical parameters accounting for the interaction. Each nonionic surfactant interacted with SDS; the relative strength of interaction depended considerably on the molecular structure of surfactants. In each instance the SDS ‐ surfactant complex was less hydrophobic than the surfactant itself. The result of PCA points to the involvement of both hydrophobic and hydrophilic forces in complex formation. The data also indicate that the apolar alkyl chain of SDS is probably bound to the hydrophobic moiety of surfactants, and the polar head group interacts with the hydrophilic ethylene oxide chain of nonionic surfactants. The strong interaction between SDS and nonionic surfactants suggests that this interaction may have a marked influence on the biological efficacy of any pharmaceutical, agrochemical formulations and cosmetics containing simultaneously both types of surfactants.
Processes Underlying Interactions of Human Lactoferrin with the Jurkat Human Lymphoblastic T‐cell Line Receptor. II ‐ Comparative Molecular Field Analysis
Authors: Elass Abdelaziz , Vergoten Gérard , Legrand Dominique , Mazurier Joël , Elass‐Rochard Elisabeth , Spik Geneviève
Published: October 2006

It has previously been established that all or part of residues 4 ‐ 52 of human lactoferrin interact with the specific T‐lymphocyte receptor. Furthermore, the preliminary study using classical quantitative structure‐affinity relationships (QSAR) models have pointed out the importance of some H‐bond donor and acceptor groups of aminoacids in the interactions. In the present paper, comparative molecular field analysis (CoMFA) was used as a three‐dimensional QSAR method to define major steric and electrostatic features of lactoferrin‐T‐lymphocyte interactions. According to steric interaction energies, some residues of human lactoferrin: R3, F20, Q23, R24, S38 and Q47, previously described by the QSAR method, as well as Q21, R27 and R56 look essential for interactions. The results of the electrostatic features study are also in good agreement with the QSAR H‐bonds model and demonstrate that the pHi is a significant binding factor. Taken as a whole, QSAR and CoMFA methods allow to define two regions, potentially involved in selectivity between species, R3, Q7, N13, Q23, R24, S38, Q50 and N55; and binding potency, P14, F20, D43, S44, P45 and Q47.
Structure and dissociation energy of weakly bound H (n = 5−8) complexes
Authors: Seo Hyun‐Il , Sun Ju‐Yong , Shin Chang‐Ho , Kim Seung‐Joon
Published: October 2006

The geometrical parameters, vibrational frequencies, and dissociation energies for H (n = 5–8) clusters have been investigated using high level ab initio quantum mechanical techniques with large basis sets. The highest level of theory employed in this study is TZ2P CCSD(T). The C1 structure of H is predicted to be a global minimum, while the Cs structure of H is calculated to be a transition state. Harmonic vibrational frequencies are also determined at the DZP and TZ2P CCSD levels of theory. The dissociation energies, De, for H (n = 5–8) have been predicted using energy differences at each optimized geometry, and zero‐point vibrational energies (ZPVEs) are considered to compare with experimental values. The dissociation energies (Do) have been predicted to be 1.69, 1.65, 1.65, and 1.46 kcal · mol for H, H, H (C1 symmetry) and H, respectively, at the TZ2P CCSD(T) level of theory. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
Quasi‐random integration in quantum chemistry: Efficiency, stability, and application to the study of small atoms and molecules constrained in spherical boxes
Authors: Cuenca D. Zorrilla , Márquez J. Sánchez , Núñez M. Fernández , Huertas R. Rodríguez
Published: October 2006

This project consists of two parts. In the first part, a series of test calculations is performed to verify that the integrals involved in the determination of atomic and molecular properties by standard self‐consistent field (SCF) methods can be obtained through Halton, Korobov, or Hammersley quasi‐random integration procedures. Through these calculations, we confirm that all three methods lead to results that meet the levels of precision required for their use in the calculation of properties of small atoms or molecules at least at a Hartree–Fock level. Moreover, we have ensured that the efficiency of quasi‐random integration methods that we have tested is Halton=Korobov>Hammersley≫pseudo‐random. We also find that these results are comparable to those yielded by ordinary Monte Carlo (pseudo‐random) integration, with a calculation effort of two orders of smaller magnitude. The second part, which would not have been possible without the integration method previously analyzed, contains a first study of atoms constrained in spherical boxes through SCF calculations with basis functions adapted to the features of the problem: Slater‐type orbitals (STOs) trimmed by multiplying them by a function that yields 1 for 0 < r < (R‐δ), polynomial values for (R‐δ) < r < R and null for r > R, R being the radius of the box and δ a variationally determined interval. As a result, we obtain a equation of state for electrons of small systems, valid just in the limit of low temperatures, but fairly simple. © 2006 Wiley Periodicals, Inc. Int J Quantum Chem, 2007
A metabonomic analysis of plasma from Zucker rat strains using gas chromatography/mass spectrometry and pattern recognition
Authors: Major Hilary J. , Williams Rebecca , Wilson Amy J. , Wilson Ian D.
Published: October 2006

Plasma obtained from three strains of Zucker rats was analysed using capillary gas chromatography/mass spectrometry (GC/MS) to obtain global metabolite profiles as part of a series of metabonomic investigations of animal models of diabetes. Samples were obtained from 20‐week‐old male wild‐type Zucker lean, (fa/fa) obese and lean/(fa) animals and were analysed following protein precipitation, using acetonitrile, and derivatisation. Subsequent data analysis using principal components analysis (PCA) and orthogonal projection to latent structures (OPLS) revealed differences between the plasma metabolite profiles of the three strains, with those of the Zucker lean and the lean/(fa) crosses being similar to each other whilst differing from the (fa/fa) obese strain. Copyright © 2006 John Wiley & Sons, Ltd.
Liquid chromatographic/tandem mass spectrometric method for the quantitation of tranilast in human plasma
Authors: Lan Jing , Wang Jian , Wu Dan , Wang Yingwu , Fawcett J. Paul , Gu Jingkai
Published: October 2006

An analytical method for the determination of tranilast in human plasma using tramadol as the internal standard has been developed based on liquid chromatography/tandem mass spectrometry. Sample preparation involved protein precipitation with methanol. Separation by reversed‐phase high‐performance liquid chromatography using methanol/10 mM ammonium acetate (70: 30, v/v) as mobile phase was complete in a run time of 2.4 min. Detection on a Q TRAP™ system used multiple reaction monitoring. The method was linear in the range 0.06–20 µg/mL with intra‐ and inter‐day precisions (as relative standard deviation) of 2.2–2.6% and 2.3–2.9%, respectively. Accuracy (as relative error) was <−2.5%. The method was applied in a pharmacokinetic study in healthy volunteers treated with a single 80 mg oral dose of tranilast. Copyright © 2006 John Wiley & Sons, Ltd.