bluuebunny/crossref_metadata_2025 huggingface dataset:
Synthesis and in Vitro Degradation of Testosterone‐Lipid Conjugates
Authors: Scriba Gerhard K. E.
Published: October 2006

Testosterone‐lipid conjugates were obtained by covalent binding of the drug to 1,3‐dipalmitoylglycerol via succinic acid to 4‐(1,3‐dipalmitoyl‐2‐glyceryl)butyric acid and to 3‐palmitoyloxy‐2‐palmitoyloxymethylpropionic acid. In contrast to the corresponding bis‐deacyl derivatives, the lipids were not significantly hydrolyzed in aqueous buffers and in plasma. Incubation with pancreatic lipase yielded primarily the bis‐deacyl compounds, which are comparable to monoglycerides, and subsequently slowly liberated testosterone. It is concluded that the lipid conjugates are substrates for pancreatic lipase. However, the drug was released very slowly due to steric hindrance.
Studien zur Chemie von thienoanellierten O,N‐ und S,N‐haltigen Heterocyclen, 9. Mitt.: Synthese und Calciumkanal blockierende Wirkung eines thienoanalogen KT‐362
Authors: Erker Thomas
Published: October 2006

Ausgehend vom Ester 5 wird über mehrere Stufen 4‐[3‐[2‐(3,4‐Dimethoxyphenyl)‐ethylamino]‐propanoyl]‐2‐ethyl‐4,5,6,7‐tetrahydrothieno[2,3‐b]‐[1,4]thiazepin (3) aufgebaut, eine thienoanaloge Verbindung zum Calciumkanalblocker KT‐362. Es wird über die Ca2+‐antagonistische Wirkung dieses Thiazepinderivats berichtet.
Untersuchungen zur Cyclokendensation von o‐aminophenyl‐substituierten Ketoximen und Amidoximen mit Carbonylverbindungen zu anellierten Chinazolinderivaten
Authors: Lessel Jürgen
Published: October 2006

o‐Aminophenyl‐substituierte Ketoxime und Amidoxime 3 reagieren mit Aldehyden und Ketonen zu cyclischen Amidin‐ bzw. Chinazolin‐N‐oxiden 5, mit Diethylcarbonat ergibt Anthranilsäureamidoxim (3c) das Oxadiazolon 12. Dieses erfährt bei der Thermolyse eine Ringtransformation zu dem Aminoindazol 14, mit Ketonen erfolgt der Ringschluß zu den anellierten Chinazolinderivaten 22. Zur Erklärung des Reaktionsverlaufs werden semiempirische Molekülorbitalverfahren und die Störungstheorie herangezogen.
Heterocyclische Spirocyclohexadienone, 3. Mitt.
Authors: Möhrle Hans , Schake Dieter
Published: October 2006

3‐Substituierte 2‐Naphtholderivate ergeben mit N‐Methyl‐2‐naphthylamin und Paraformaldehyd in guten Ausb. entspr. Spirocyclohexadienone, wobei auch 9‐Phenanthrol diesem Reaktionstyp zugänglich ist. Grundsätzlich liefern 4‐substituierte 1‐Naphthole ebenfalls Spiroketone, die jedoch labiler sind und in geringerem Ausmaß anfallen. Die Umsetzung der Spirocyclohexadienone mit Protonensäuren, Carbonylreagenzien und komplexen Hydriden wird untersucht und hieraus ein Reaktionsmechanismus abgeleitet.
Inhaltsstoffe tropischer Arzneipflanzen, 67. Mitt.: 24‐Acetylaminofevicordin D‐glucosid, ein artefizieller Inhaltsstoff von Fevillea cordifolia? — Zur Reaktivität der Fevicordine
Authors: Achenbach Hans , Horn Konrad , Waibel Reiner
Published: October 2006

24‐Acetylaminofevicordin D‐glucosid (1) wurde als neue Nebenkomponente aus den Samen von Fevillea cordifolia (Cucurbitaceae) isoliert und seine Struktur mit spektroskopischen Methoden aufgeklärt. Wie Experimente zeigten, reagiert das Enon‐System in der Seitenkette von Fevicordin A‐glucosid (2), dem Hauptinhaltsstoff der Samen, mit Nucleophilen in einer Michael‐Addition. Mit Ammoniak verläuft diese Reaktion besonders leicht, wobei gleichzeitig die Acetylgruppe vom Sauerstoff an C‐25 zum Stickstoff wandert. 1 muß daher möglicherweise als Artefakt angesehen werden.
Third Generation Antitumor Platinum(II) Complexes of the [1‐(Fluoro/difluorophenyl)‐2‐phenylethylenediamine]platinum(II) Type
Authors: Gust Ronald , Schönenberger Helmut
Published: October 2006

The diastereomeric 1‐(fluoro/difluorophenyl)‐2‐phenylethylenediamines (4‐fluoro: erythro‐1/threo‐1; 2,4‐difluoro: erythro‐2/‐threo‐2; 2,6‐difluoro: erythro‐3/threo‐3) and the diastereomeric 1‐(4‐fluorophenyl)‐2‐(3‐hydroxyphenyl)ethylenediamines (erythro‐4/‐threo‐4) were synthesized from appropriately substituted stilbenes by reaction with IN3 and subsequent LiAlH4 reduction. Coordination of the 1,2‐diphenylethylenediamines to platinum was carried out by use of K2PtI4. The water‐soluble aquasulfatoplatinum(II) complexes (erythro/threo‐1‐PtSO4‐erythro/threo‐4‐PtSO4) were obtained from the diiodoplatinum(II) complexes by reaction with Ag2SO4. Additionally erythro/threo‐4‐PtSO4 and erythro/threo‐4‐PtSO4 were transformed into the dichloroplatinum(II) complexes (erythro/threo‐1‐PtCl2, erythro/threo‐4‐PtCl2) by treatment with KCl. In contrast to the less effective erythro‐configurated sulfatoplatinum(II) complexes the threo‐analogues showed comparable or even superior activities to cisplatin on the human MDA‐MB‐231 breast cancer cell line. On the MXT‐M‐3.2 breast cancer of the mouse only erythro‐ and threo‐4‐PtSO4 caused similar effects like cisplatin. The strong inhibitory effect of the diastereomeric sulfatoplatinum(II) complexes on the P‐388 leukemia of the mouse was equal to that of cisplatin. On the latter tumor threo‐4‐PtCl2 was the most active among the less toxic dichloroplatinum(II) derivatives.
Synthesis, Pharmacological Investigation and Computational Studies on a Tricyclic Ergoline Analog with Selective Dopamine Autoreceptor Activity
Authors: Gmeiner Peter , Bollinger Bernd , Mierau Joachim , Höfner Georg
Published: October 2006

The novel aminobenzindolone 8 was prepared and evaluated as a potential antipsychotic agent. The target compound was synthesized in eight steps starting from the tetrahydrobenzindolone 9. The key step of the synthesis was an electrophilic amination of the aromatic ketone 11 followed by reductive degradation when the diethoxymethyl group was employed for protection of the lactam nitrogen and also for the benzylic position 2a. Dopamine and serotonin receptor binding studies revealed 8 to be a potent and selective ligand at the D‐2 autoreceptor (ki = 4.0 nM). Further in vivo studies including the GBL‐test and locomotor activity measurements indicated agonistic activity of 8 at the prejunctional binding sites. Comparison of ab initio based molecular electrostatic isopotential maps corroborates our hypothesis that the dopamine structure 6, containing an intramolecular hydrogen bond donating effect of the meta‐HO‐group, represents the conformation which is active at the dopamine D‐2 autoreceptor.
Chemotactic Peptide Analogues. Synthesis and Chemotactic Activity of N‐Formyl‐Met‐Leu‐Phe Analogues Containing (S)‐Phenylalaninol Derivatives
Authors: Zecchini Giampiero Pagani , Paradisi Mario Paglialunga , Torrini Ines , Spisani Susanna
Published: October 2006

The synthesis and the biological activity towards human neutrophils of some N‐formyl‐Met‐Leu‐Phe‐OMe analogues containing (S)‐phenylalaninol (Pheol) or its derivatives in place of the native phenylalanine are reported. While the analogue containing Pheol (4) was found to be devoid of significant biological activity, its esters 3 and 5, although inactive as chemoattractants, are able to strongly stimulate superoxide production and are active with a lower efficacy in the lysozyme release.
Synthesis of New 2‐{[(Phenoxy or Phenyl)acetyl]amino}benzoic Acid Derivatives as 3α‐Hydroxysteroid Dehydrogenase Inhibitors and Potential Antiinflammatory Agents
Authors: Daidone Giuseppe , Plescia Salvatore , Bajardi Maria Luisa , Schillaci Domenico
Published: October 2006

A number of 2‐{[(phenoxy or phenyl)acetyl]amino}benzoic acid derivatives were prepared in about 50% yield from (phenoxy or phenyl)acetyl chloride and anthranilic acid derivatives. All the compounds were tested as in vitro inhibitors of 3α‐hydroxysteroid dehydrogenase, since enzyme inhibition predicts potential antiinflammatory activity in vivo The most active compounds 3 1, m, s are about 3.5 times more active than acetylsalicylic acid (ASA). Activity is influenced by electronic as well as steric effects.
Anti‐Elastase and Anti‐Hyaluronidase Activities of Saponins and Sapogenins from Hedera helix, Aesculus hippocastanum, and Ruscus aculeatus: Factors Contributing to their Efficacy in the Treatment of Venous Insufficiency
Authors: Facino Roberto Maffei , Carini Marina , Stefani Rita , Aldini Giancarlo , Saibene Luisella
Published: October 2006

Triterpene and steroid saponins and sapogenins of medicinal plants (Aesculus hippocastanum L., Hedera helix L., Ruscus aculeatus L.) are claimed to be effective for the treatment/prevention of venous insufficiency. In this work we evaluated the inhibitory effects of these plant constituents on the activity of elastase and hyaluronidase, the enzyme systems involved in the turnover of the main components of the perivascular amorphous substance.

The results evidence that for Hedera helix L., the sapogenins only non‐competitively inhibit hyaluronidase activity in a dose‐dependent fashion, showing comparable IC50 values (hederagenin IC50 = 280.4 μM; oleanolic acid IC50 = 300.2 μM); both the saponins hederacoside C and α‐hederin are very weak inhibitors.

The same behaviour is observed for serine protease porcine pancreatic elastase: the glycosides are devoid of inhibitory action, while genins are potent competitive inhibitors (oleanolic acid IC50 = 5.1 μM; hederagenin IC50 = 40.6 μM). Constituents from Aesculus hippocastanum L. show inhibitory effects only on hyaluronidase, and this activity is mainly linked to the saponin escin (IC50 = 149.9 μM), less to its genin escinol (IC50 = 1.65 μM).

By contrast, ruscogenins from Ruscus aculeatus L., ineffective on hyaluronidase activity, exhibit remarkable anti‐elastase activity (IC50 = 119.9 μM; competitive inhibition). The mechanism of elastase inhibition by triterpene and steroid aglycones, with a nitroanilide derivative as substrate, is discussed.
Peroxides as Constituents of Plants, Part 19: A C50‐Hydroperoxide from Hypericum perforatum
Authors: Rücker Gerhard , Manns Detlef , Hartmann Rudolf , Bonsels Ulrike
Published: October 2006

A new C50‐hydroperoxide (1) with a hitherto unknown constitution, containing cadinane hydroperoxide and hyperforin (2) as partial structures, was isolated from the stems and leaves of St. John's wort (Hypericum perforatum L., Hypericaceae). The structure was elucidated by high‐resolution NMR techniques (1D and 2D NMR experiments).
Platelet Aggregation Inhibiting and Anticoagulant Effects of Oligoamines, Part 31: Distribution Behaviour of 131‐Iodine Labelled trans‐N,N′‐Bis‐(ethoxy‐carbonyl)‐N‐[4‐(3‐iodo‐4‐methoxyphenyl)butyl]‐N′‐5‐phenylpentyl)‐1,4‐cyclohexanedimethanamine
Authors: Rehse Klaus , Wolf Stefan , Buck Wolfgang , Wenzel Martin
Published: October 2006

The title compound 9, which is a prodrug, and its active metabolite 7 were labelled with 131I (7*/9*) to investigate their pharmacokinetic behaviour, including the distribution between stomach, gut, muscle, blood, lung, liver, kidney, adrenal gland, heart, and spleen. Four hours after oral administration of 7* to mice only 3% of the dose had been absorbed from the g.i. tract. After 24 h 54 % of the radioactivity still is found the gut, predominantly in the small intestine. These results explain why 7, which is a potent antiplatelet drug in vitro, shows no antithrombotic effect in vivo. In contrast, the produg 9/9* is absorbed considerably, i.e. up to 50 % in 4 h from the g.i. tract depending on the dose applied and the vehicle used. At doses in the micromolar range the absorption appears to be diffusion limited. The highest concentrations are found in the liver and the kidneys suggesting a first pass effect of 7 followed by renal excretion. From the blood levels achieved, the dose nessessary for an antithrombotic effect has been calculated to be about 100 mg/kg. In summary, the N‐ethoxycarbonyl derivatives of oligoamines appear to be suitable prodrugs for oral administration of oligoamines.
Synthesis and Calcium Channel Modulating Effects of Alkyl 1,4‐Dihydro‐2,6‐dimethyl‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐(1H‐tetrazol‐5‐yl)‐3‐pyridinecarboxylates
Authors: Iqbal Nadeem , Knaus Edward E.
Published: October 2006

A group of racemic alkyl 1,4‐dihydro‐2,6‐dimethyl‐4‐(pyridinyl or 2‐trifluoromethylphenyl)‐5‐(1H‐tetrazol‐5‐yl)‐3‐pyridinecarboxylates 11–14 were prepared using the Hantzsch reaction that involved the condensation of 2‐, 3‐ or 4‐pyridinecarboxaldehyde, or 2‐trifluoromethylbenzaldehyde, 8a–d with isopropyl or methyl 3‐aminocrotonate (9a–b) and 5‐(2‐oxopropyl)‐1H‐tetrazole (10a) or 5‐(2‐oxopropyl)‐1‐methyl‐1H‐tetrazole (10b). In vitro calcium channel (CC) antagonist and agonist activities were determined using guinea pig ileum longitudinal smooth muscle (GPILSM) and guinea pig left atrium (GPLA) assays, respectively. In the series of compounds 11–14, only compounds 14a and 14b exhibited some weak CC antagonist activity (10−6 M range) relative to the reference drug nifedipine (IC50 = 1.43 × 10−8 M). Compounds 11b‐14b having a 1‐methyl‐1H‐tetrazol‐5‐yl substituent were inactive CC agonists on GPLA. In contrast, compounds 12a‐14a having a 1H‐tetrazol‐5‐yl substituent exhibited CC agonist activity on GPLA, but the C‐4 2‐pyridinyl analog 11a exhibited a mild negative inotropic effect. The approximately equipotent CC agonist activity (GPLA) exhibited by the C‐4 pyridinyl 13a and 4‐(2‐trifluoromethylphenyl) 14a compounds compared favorably with that of the reference drug (±)‐Bay K 8644 (EC50 = 7.7 × 10−7 M) indicating that the 1H‐tetrazol‐5‐yl moiety is a suitable replacement for the nitro group present in Bay K 8644 with respect to cardiac CC agonist activity. These latter compounds 13a and 14a should serve as useful probes to study the structure‐function relationships of calcium channels.
Sensitizing Properties of New N‐(2‐Arylalkyl) Propionamides in Drug‐Sensitive and Multidrug‐Resistant Tumor Cells
Authors: Ros Francisco , García Rocío , Rivera‐Fillat Maria Pilar , González Miguel A. , Grau‐Oliete Maria Rosa
Published: October 2006

The propionamides 5 and 6 have been synthesized and tested for stimulation of antitumor drug activity. 5 and 6b increase vincristine cytotoxicity in drug‐sensitive murine tumor cells; 5 also increases the toxicity in multidrug resistant cells. Dissimilar trends in sensitive and resistant cells have been observed for the stimulating activity of several propionamides of this family and structurally related verapamil with their molar refractivity, suggesting different size requirements for the sensitizers in sensitive and resistant cells.
New NO‐Donors with Antithrombotic and Vasodilating Activities, Part 13: Pyrazol‐4‐one 1,2‐Dioxides and 4‐Hydroxyiminopyrazole 1,2‐Dioxides
Authors: Rehse Klaus , Müller Ulrich
Published: October 2006

Twenty pyrazol‐4‐one 1,2‐dioxides and eleven 4‐hydroxyiminopyrazole 1,2‐dioxides were prepared and tested for their antiplatelet activity (Born test with collagen). Six compounds which all belong to the pyrazolone series inhibited the platelet aggregation half‐maximally in submicromolar concentrations (200–800 nmol/L). In positions 3 and 5, these compounds bear at least one (15, 16, 24, 31) or two substituents (7, 29) with electron‐withdrawing groups. Among them are aromatic moieties like 4‐hydroxysulfonylphenyl (7), 4‐cyanophenyl (16), 4‐chlorophenyl (15), phenyl (24) or carboxylic acid esters (29). Two compounds were investigated in an in vivo thrombosis model (1, 31). 2h after oral administration of 60 mg/kg 1 to rats in arterioles 69 % inhibition of thrombus formation (venules 40 %) was observed.
(2E,4E)‐N‐(4‐(1H‐Indol‐3‐yl)piperidin‐1‐yl)alkyl‐5‐(substituted phenyl)‐2,4‐pentadienamides as Antiallergic Agents with Antihistaminic and Anti Slow‐Reacting Substance (SRS) Activities
Authors: Shigenaga Shinji , Manabe Takashi , Matsuda Hiroshi , Fujii Takashi , Matsuo Masaaki
Published: October 2006

As an extension of our study aiming to discover a novel compound with dual activities against histamine and slow‐reacting substance (SRS), we synthesized two types of indolylpiperidine derivatives, 3 and 4–20. Testing for in vivo antianaphylactic activity and for in vitro anti‐SRS activity revealed that (2E,4E)‐5‐(3,5‐dimethoxy‐4‐hydroxyphenyl)‐N‐(2‐(4‐(1H‐indol‐3‐yl)piperidin‐1‐yl)ethyl)‐2,4‐pentadienamide (11) exhibited potent dual activities with ED50 = 0.89 mg/kg and IC50 = 1.43 μM, respectively. However, the plasma concentration of unchanged 11 was very low when administered orally in guinea pigs. This result can be explained by fast formation of a glucuronic acid conjugate.
Reduced Flexibility Analogs of Analgesic and Cognition Enhancing α‐Tropanyl Esters
Authors: Manetti Dina , Romanelli Maria Novella , Bartolini Alessandro , Dei Silvia , Ghelardini Carla , Gualtieri Fulvio , Matucci Rosanna , Scapecchi Serena , Teodori Elisabetta
Published: October 2006

A series of semirigid analogs of compounds 1 and 2, two potent analgesics and cognition enhancers, have been synthesized and tested for antinociceptive activity (hot plate test) and for muscarinic affinity (binding in rat cerebral cortex). They were found to be in general less potent than the reference compounds; only one of them (22) shows a good affinity for the muscarinic receptor and an antinociceptive efficacy comparable with those of the reference compounds. At a dose of 30 mg/kg 22 is also able to reverse the amnesic effect of dicyclomine. Since the analgesic effect of these compounds is affected by the 5‐HT4 antagonist SDZ 205557, the possible role of this receptor is discussed.
Benzimidazole‐type Glycine Antagonists: The Role of the Ring Nitrogen Atoms
Authors: Berger Michael L. , Schödl Clemens , Noe Christian R.
Published: October 2006

Several derivatives of 1H‐benzimidazole‐2‐carboxylic acid (BICA, 2a) were tested in vitro in comparison to 1H‐indole‐2‐carboxylic acid (ICA, 1e) for their ability to displace [3H]glycine from rat hippocampal membranes. Compound 2a was 8 times more potent than 1e (Ki 5.3 μM, as compared to 42 μM). However, introduction of a carboxymethyl group or a corresponding ester at position 3 had no positive effect on the potency of 2a, while this type of structural modification increased the potency of 1e significantly. Nevertheless, 1‐carboxymethyl‐BICA (2b) displaced [3H]glycine with similar potency as the corresponding 3‐carboxymethyl‐ICA 1c, indicating that also a nitrogen atom lacking a hydrogen atom can be engaged in glycine receptor interaction. N‐Methylation strongly reduced the potencies of both BICA and ICA derivatives.
Chemotactic Peptide Analogues The Role of (Z)‐2,3‐Didehydrophenylalanine and Phenylalanine C‐Terminal Residues in Determining the Chemotactic Activity of Formylpeptides
Authors: Torrini Ines , Zecchini Giampiero Pagani , Paradisi Mario Paglialunga , Spisani Susanna
Published: October 2006

Several formylpeptides, analogs of the chemotactic agent HCO‐Met‐Leu‐Phe‐OMe, having the HCO‐Xaa‐Leu‐ΔzPhe‐OMe and HCO‐Xaa‐Leu‐ΔzPhe‐Phe‐OMe structures (ΔzPhe = (Z)‐2,3‐didehydrophenylalanine), have been synthesized. The biological activity of these ligands has been determined on human neutrophils and compared to that of the corresponding HCO‐Xaa‐Leu‐Phe‐OMe derivatives not containing the unsaturated residue. The replacement of the C‐terminal Phe with ΔzPhe causes, in all the examined tripeptides, the loss of any biological activity. On the other hand, the introduction into the ΔzPhe containing models of an additional C‐terminal Phe residue leads to the formyltetrapeptides HCO‐Xaa‐Leu‐ΔzPhe‐Phe‐OMe which show a biological activity very similar to that exhibited by the corresponding HCO‐Xaa‐Leu‐Phe‐OMe analogues.
New Potent Azomethine Prodrugs of the Histamine H3‐Receptor Agonist (R)‐α‐Methylhistamine Containing a Heteroarylphenyl Partial Structure
Authors: Krause Michael , Rouleau Agnès , Stark Holger , Luger Peter , Garbarg Monique , Schwartz Jean‐Charles , Schunack Walter
Published: October 2006

The therapeutic value of histamine H3‐receptor ligands is under current investigation. On the basis of recently described diaryl imine prodrugs of the histamine H3‐receptor agonist (R)‐α‐methyl‐histamine (1) a series of new azomethine prodrugs containing five‐ and six‐membered heterocycles were synthesized and tested for their in vitro hydrolysis rates and in vitro activity after oral application. It was found that electron‐deficient six‐membered heterocycles drastically destabilized the imine double bond so that these prodrugs decomposed unsuitably fast. On the contrary, prodrugs containing five‐membered heterocycles appeared to be highly effective for the CNS delivery of 1, and a remarkable correlation between chemical structure and pharmacokinetic profile was observed. Particularly (R)‐4‐fluoro‐2‐[[N‐[1‐(1H‐imidazol‐4‐yl)‐2‐propyl]imino](1H‐pyrrol‐2‐yl)methyl]phenol (8c), the 2‐furanyl analogue 8d, and its 3‐furanyl isomer 8e proved to be equipotent to the most potent of recently described halogenated diaryl imine prodrugs of 1. However, in contrast to any other azomethine prodrug, 8c exhibited an incomparably long lasting delivery of 1 in the CNS and can thus be regarded as a ‘retard’ prodrug. Assuming that a therapeutic indication of histamine H3‐receptor agonists will soon be established, these highly potent heteroarylphenyl azomethine prodrugs, which already serve as valuable pharmacological tools, may also become potential drugs in clinical use.
Synthesis and Antimicrobial Activity of New Quaternary Ammonium Chlorides
Authors: Brycki Bogumil , Skrzypczak Andrzej , Mirska Ilona , Pernak Juliusz
Published: October 2006

Decyldimethylamine reacts readily with chloromethylalkyl ethers or sulfides, chloromethylbezyl ethers or sulfides and chloromethylcycloalkyl ethers to give quaternary ammonium chlorides in very good yields. All the chlorides studied showed antimicrobial activity. The relationship between the chemical structure and antimicrobial activity was analyzed by rough sets.
Search for the Pharmacophore in Kappa‐agonistic Diazabicyclo[3.3.1]nonan‐9‐one‐1,5‐diesters and Arylacetamides
Authors: Brandt Wolfgang , Drosihn Susanne , Haurand Michael , Holzgrabe Ulrike , Nachtsheim Corina
Published: October 2006

Several heterocyclic bicyclo[3.3.1]nonan‐9‐ones were found to have a high affinity to k opioid receptors. 3,7‐Diazabicyclononanones with 2,4‐dipyridyl side chains were the most potent agonists whereas the corresponding 3‐oxa‐7‐azabicyclo[3.3.1]nonan‐9‐one and compounds with phenyl substituents in 2 and 4 position are almost inactive. The purpose of this study was to unravel the active conformation of the bicyclononanones using well‐known k‐selective agonists such as ketocyclacocine, arylacetamides, several isoquinolines, CI‐977, and four stereoisomers of EMD‐61753 for comparison. In order to determine the geometry of the diazabicycles in solution pH‐dependent NMR measurements of the bicycles were recorded and the results were related to the geometries of the aforementioned k agonists obtained from semiempirical PM3 calculations. A chair‐boat conformation and a protonation at the N7 nitrogen atom of the diazabicyclononanones were found to be the pharmacophoric conformation. Comparison of the spatial arrangements, electrostatic, hydrophobic, and hydrogen bonding potentials of all k‐selective agonists led to a model of structure‐activity relationships of ligands of the k‐receptor. The arrangement of the pharmacophoric elements is characterized by an almost parallel orientation of a carbonyl and a protonated NH function in conjunction with at least one aromatic ring. Ketocyclazocine is only able to adopt this parallel orientation when the nitrogen is inverted relative to the X‐ray structure. Furthermore, two binding sites for the aromatic rings are discussed. The pharmacological results of all considered bicyclononanone derivatives as well as of the four enantiomers of EMD‐61753 can be understood and consistently explained in this way.
3‐(Octadecanoylaminomethyl)indole‐2‐carboxylic Acid Derivatives and 1‐Methyl‐3‐octadecanoylindole‐2‐carboxylic Acid as Inhibitors of Cytosolic Phospholipase A2
Authors: Lehr Matthias
Published: October 2006

3‐(1‐Acylaminooctadecyl)indole‐2‐carboxylic acids and 3‐(1‐acylaminooctadecyl)‐1‐methylindole‐2‐carboxylic acids were designed and synthesized as inhibitors of cytosolic phospholipase A2. Enzyme inhibition was assayed by evaluation of calcium ionophore A23187‐induced arachidonic acid release from bovine platelets. While compounds with 1‐octadecanoylaminooctadecyl groups in position 3 of the indole were inactive inhibition data for 3‐[1‐(3‐phenylpropionylamino)octadecyl]indole‐2‐carboxylic acids could not be evaluated because of lysis of the platelets. However 3‐(octadecanoylaminomethyl)indole‐2‐carboxylic acid derivatives and 1‐methyl‐3‐octadecanoylindole‐2‐carboxylic acid proved to be inhibitors of cytosolic phospholipase A2. The most active inhibitor was the latter compound with an IC50 of 8 μM.
The Potential of Aspirin in Prodrug Synthesis: A New Potential Delivery System of AZT and FLT
Authors: Zahran Magdy A. , Kovács Lajos , Sakka Ibrahim El , Pedersen Erik B. , Nielsen Claus
Published: October 2006

Aspirin (O‐acetylsalicylic acid) has been used to synthesize prodrugs of 3′‐azido‐3′‐deoxythymidine (AZT) and 3′‐deoxy‐3′‐fluorothymidine (FLT). The mixed anhydride between aspirin and trifluoroacetic acid was synthesized and reacted with AZT and FLT to give the blocked nucleosides attached through the 5′‐O position to the 2‐position of 2‐methyl‐4H‐1,3‐benzodioxin‐4‐one. The prodrugs showed the same activities against HIV‐1 in MT‐4 cells as the original drugs. Hydrolysis of the synthesized prodrugs in the growth medium, used for anti‐HIV investigations, resulted in formation of 5‐O acetylated drugs which were subsequently hydrolyzed into the original drugs.
Novel Steroidal 1,4‐Diketones and Pyridazine Derivatives as Potential Antiestrogens
Authors: Ismail Khadiga A. , El‐Tombary Alaa A. , Aboulwafa Omaima M. , Omar A‐Mohsen M. E. , El‐Rewini Safaa H.
Published: October 2006

A series of steroidal 1,4‐diketone derivatives was synthesized by acid‐catalyzed condensation of 2‐acetylestradiol‐17β‐acetate with substituted phenylglyoxals. Conversion of the products into the corresponding pyridazine derivatives was achieved by reaction with hydrazine hydrate. The synthesized compounds were evaluated for their uterotrophic, antiuterotrophic, and antifertility activities in mature female albino rats. Among the compounds tested, the phenyl 2, p‐bromophenyl 3, and p‐methoxyphenyl 5 diketone derivatives displayed uterotrophic activity of 72%, 72%, and 91%, respectively. The gradation of antiestrogenic activity was assessed in vivo by the inhibition of the estrone‐stimulated uterine growth. Compounds 2–5 showed moderate antiestrogenic activity of 53–56%. None of the tested compounds elicited antifertility activity as assessed by the post‐coital antiimplantation activity test.
Synthesis and Antifungal Activities of Myristic Acid Analogs
Authors: Parang Keykavous , Knaus Edward E. , Wiebe Leonard I. , Sardari Soroush , Daneshtalab Mohsen , Csizmadia Ferenc
Published: October 2006

Myristic acid analogs that are putative inhibitors of N‐myristoyl‐transferase were tested in vitro for activity against yeasts (Saccharomyces cerevisiae, Candida albicans, Cryptococcus neoformans) and filamentous fungi (Aspergillus niger). Several (±)‐2‐halotetradecanoic acids including (±)‐2‐bromotetradecanoic acid (14c) exhibited potent activity against C. albicans (MIC = 39 μM). C. neoformans (MIC = 20 μM), S. cerevisiae (MIC = 10 μM), and A. niger (MIC < 42 μM) in RPMI 1640 media. Improved synthetic methods have been developed for the synthesis of 12‐fluorododecanoic acid (12a) and 12‐chlorododecanoic acid (12c). Three novel fatty acids, 12‐chloro‐4‐oxadodecanoic acid (8a), 12‐phenoxydodecanoic acid (12i), and 11‐(4‐iodophenoxy)undecanoic acid (13d) were also synthesized and tested.
3‐(3,5‐Dimethyl‐4‐octadecanoylpyrrol‐2‐yl)propionic Acids as Inhibitors of 85 kDa Cytosolic Phospholipase A2
Authors: Lehr Matthias
Published: October 2006

3‐(1,4‐Diacylpyrrol‐2‐yl)propionic acids were designed as inhibitors of cytosolic phospholipase A2. Enzyme inhibition was assayed by evaluation of calcium ionophore A23187‐induced arachidonic acid release from bovine platelets. While the synthesized bisacyl compound 3‐[3,5‐dimethyl‐4‐octadecanoyl‐1‐(3‐phenylpropionyl)pyrrol‐2‐yl]propionic acid was inactive at 33 μM, the related monoacylated 3‐(3,5‐dimethyl‐4‐octadecanoylpyrrol‐2‐yl)propionic acid and 3‐(1,3,5‐trimethyl‐4‐octadecanoylpyrrol‐2‐yl)propionic acid proved to be inhibitors of cytosolic phospholipase A2 (IC50: 24 μM and 13 μM, respectively).
Synthesis and Activity of the Glutathione Analogue γ‐(L‐γ‐Oxaglutamyl)‐L‐cysteinyl‐glycine
Authors: Calcagni Anna , Duprè Silvestro , Lucente Gino , Luisi Grazia , Pinnen Francesco , Rossi Domenico , Spirito Alessandra
Published: October 2006

An efficient synthesis of the backbone modified glutathione analogue γ‐(L‐γ‐oxaglutamyl)‐L‐cysteinyl‐glycine (7), characterized by the presence of an urethane O‐CO‐NH linkage replacing the γ‐glutamylic CH2CO‐NH fragment is described. The new analogue has been fully characterized by 1H‐ and 13C‐NMR, and FAB‐MS. Compound 7 was tested for inhibition of γ‐glutamyl‐transferase activity and was found to be a non‐competitive inhibitor of hog kidney γ‐glutamyltransferase (EC 2.3.2.2).
Effect of Guaiazulene on Some Cytochrome P450 Activities. Implication in the Metabolic Activation and Hepatotoxicity of Paracetamol
Authors: Kourounakis Angeliki P. , Rekka Eleni A. , Kourounakis Panos N.
Published: October 2006

The in vitro and in vivo effect of guaiazulene, a natural azulene derivative, on rat hepatic cytochrome P450 (CYP) is investigated. Furthermore, paracetamol hepatotoxicity is induced in rats and the activity of specific cytochrome P450 forms, involved in the metabolic activation of paracetamol to the toxic metabolite N‐acetyl‐p‐benzoquinone imine (NAPQI) is examined, after the administration of guaiazulene, using diagnostic cytochrome P450 substrates. It is found that guaiazulene inhibited considerably CYP1A2 and CYP2B1 and had a weak effect on CYP1A1 in rat hepatic microsomal fractions. Guaiazulene administered to rats did not produce any macroscopic toxic effect and caused no change of liver weight, microsomal protein and total cytochrome P450 content. Guaiazulene inhibited CYP1A2 activity in rats with or without paracetamol intoxication. Considering that CYP1A2 participates in the formation of NAPQI, as well as in the metabolic activation of several toxic and carcinogenic compounds, these results, in combination with the antioxidant activity of guaiazulene that we have found in previous investigations, indicate potential useful applications of guaiazulene.
Carbohydrate Natural Products as a Scaffolding for the Preparation of Potential Neuraminidase Inhibitors
Authors: Maione Anna M. , Giordani Emma , Costa Mara , Spirito Alessandra
Published: October 2006

Compound 10b, 6‐acetamido‐6,8‐dideoxy‐D‐erythro‐β‐D‐galacto‐octopyranosyl‐1‐oxyacetic acid sodium salt, was synthesised by hydrazinolysis of Lincomycin, acetylation of methylthiolincosaminide (MTL) 9a, and by subsequent glycosylation of acetate 9b with methyl glycolate under mild conditions (NIS/TfOH). The methyl ester 10a was hydrolysed by treatment with Amberlite Ira‐4OO (OH−) resin and aqueous sodium hydroxide, followed by neutralisation with Dowex‐50 W × 8 (H+) resin and lyophilisation to give 10b. This carboxylate may represent the first derivative in a novel series of sialidase inhibitors utilising carbohydrate natural products. The phosphonate 11c, prepared under the same experimental conditions with dibenzyl(hydroxy‐methyl) phosphonate as acceptor, also displays an inhibitory activity towards Clostridium perfringens sialidase (Ki in mM range as with Neu5Ac).
Synthesis and Biological Evaluation of a Series of Quinazoline‐2‐carboxylic Acids and Quinazoline‐2,4‐diones as Glycine‐NMDA Antagonists: A Pharmacophore Model Based Approach
Authors: Colotta Vittoria , Catarzi Daniela , Varano Flavia , Cecchi Lucia , Filacchioni Guido , Galli Alessandro , Costagli Chiara
Published: October 2006

The synthesis and glycine‐NMDA binding activity of a series of quinazoline‐2‐carboxylic acids 1 and quinazoline‐2,4‐diones 2, containing all the essential and optional pharmacophoric descriptors required by a putative glycine antagonist model, are reported. The binding results show that only three of the title compounds displayed micromolar receptor affinity, demonstrating how disappointing the synthesis of receptor ligands based only on interaction models can be.
Microsomal Catalyzed N‐Hydroxylation of Guanfacine and Reduction of N‐Hydroxyguanfacine
Authors: Clement Bernd , Demesmaeker Mark
Published: October 2006

Guanfacine 1 is a well known centrally acting α2‐adrenoceptor agonist with antihypertensive activity. The drug belongs to the guanidine class of compounds. The N‐oxidative biotransformation of guanfacine was investigated in vitro in the presence of hepatic microsomal fractions from rabbits, pigs, and humans. The N‐hydroxylated derivative N‐hydroxyguanfacine 2 had to be synthesized as reference for the identification of the metabolite. The corresponding in vitro retroreduction of N‐hydroxyguanfacine 2 was also investigated using the same set of enzyme sources. A new HPLC analytical method was developed in order to isolate and quantify the metabolites. A complete metabolic cycle involving the oxidative metabolism of guanfacine could only be observed in the presence of microsomal fractions from rabbit livers, whereas enzyme sources of all species under investigation catalyzed the N‐reduction of N‐hydroxyguanfacine 2.
Synthesis and Structure Elucidation of 5‐Aminomethinimino‐3‐methyl‐4‐isoxazolecarboxylic Acid Phenylamides and Their Immunological Activity
Authors: Ryng Stanislw , Machón Zdzislw , Wieczorek Zbigniew , Zimecki Michal , Glowiak Tadeusz
Published: October 2006

A series of 5‐aminomethinimino‐3‐methyl‐4‐isoxazolecarboxylic acid phenylamides 4 has been prepared by condensation of 5‐amino‐3‐methyl‐4‐isoxazolecarboxylic acid phenylamides 1 with trichloroacetic aldehyde. Alcoholysis of trichloro derivatives 2 gave 5‐alkoxymethine derivatives 3 which, on reaction with an appropriate amine, formed the corresponding compounds 4. The compounds obtained were evaluated for their immunological activity. The properties of three compounds, described in this report, permitted inhibition of the immune response in all possible ways: diminishing both types of immune response (4d), humoral immune response (4a), or cellular immune response (4c). Preparation 4d is comparable in its effectiveness to CsA, so it may be potentially used as an agent for prolongation of the function of transplanted organs. Two other compounds may potentially be used in cases where only one type the immune response is required for combating pathogen invasion.
Naturwissenschaft und Religion in den Niederlanden um 1600
Authors: Snelders Harry A. M.
Published: October 2006

Dutch science flourished in the late sixteenth and in the seventeenth century thanks to the immigration of cartographers, botanists, mathematicians, astronomers and the like from the Southern Netherlands after the Spanish army had captured the city of Antwerp in 1585, and thanks to the religious and the socio‐economic situation of the country. A strong impulse for practical scientific activities started from the Reformation, mainly thanks to its anti‐traditional attitude, which had an anti‐rationalistic tendency. Therefore, in the Northern Netherlands there was no ‘warfare’ between science and religion and the biblical arguments leading to Galileo's condemnation were not used.

Although the growth of the exact sciences and of technology in the late sixteenth and the seventeenth centuries in Protestant cirles may be partly attributed to the expansion of trade, industry, navigation and so on, this does not explain why there was also at the same time a great interest in subjects as botany and zoology, which had no immediate economic utility. There were discussions about Copernicanism and Cartesianism. So a number of astronomers and theologians rejected the earth's movement on scientific and religious grounds, but there were also those who did not reject the Copernican system on biblical grounds. In the seventeenth century there was much discussion between science and religion in the Northern Netherlands, but that discussion was not followed by censure by the Church of the State. In the Republic there was a large amount of intellectual freedom in the study of the natural sciences, thanks to practical and ideological considerations. In the eighteenth century the seventheenth century tension between science and religion changed into a physicotheological natural science. It was believed that investigations into the workings of nature should lead to a better understanding of its Creator. So Bernard Nieuwentijt in his well‐known book:The right use of‐world views for the conviction of atheists and unbelievers(1715) intended to prove the existence of God on the basis of teleological arguments.
Wissenschaft und Reformation Die Beispiele der Universitäten Königsberg und Helmstedt
Authors: Pozzo Riccardo
Published: October 2006

The paper considers the development of physics‐teaching at the universities of Königsberg (founded 1544) and Helmstedt (founded 1576). The question is: How many teachers of physics professed Aristotelianism and how long? and why did most of them reject Copernicanismus? The paper suggests that Melanchthon, not only the founder of early German philosophy ‘was also the propounder of a form of, modern Aristotelianism’ which proved very valuable in mediating between theologians and philosophers on the one side and between philosophers and experimentalists on the other side.
Vernunft versus Offenbarung im Spannungsfeld von Aufklärung und Pietismus
Authors: Schenk Günter
Published: October 2006

How is the problem of science and theology perceived at a University foundet by representatives of the pietist Aufklärung (enlightenment)? The following paper describes three historical approaches which are suggested to answer this question. The author presents and investigates especially Georg Friedrich Meier's middle course (Mittelweg), which mediates (Vermittlung) between extremes.
Einfluß der Chemischen Industrie auf den Chemieunterricht Abriß einer historischen Entwicklung
Authors: Franik Roland
Published: October 2006

This historical inquiry into the enfluence with the Chemical Industriy and the chemistry education at German classical stateschools is described since the revolution of 1848. The introduction of chemistry lessons at German classical stateschools step by step is further observed between 1882 and 1901. Specially the author gives a comprehensive survey about the development after the World War II.
Wissenschaft und Krieg
Authors: Ash Mitchell G.
Published: October 2006

The essay suggests ways in which the general history of warfare in its military, social and cultural dimensions might be brought together with the historical discussion of science, technology and war in the modern era. The thesis is advanced that more is involved than the use of science as a mere instrument for the development of weapons technology. Rather, developments fundamental to modernity itself are at work: a loss of inhibition in interacting with nature; the industrialisation of warfare, including specialisation and professionalisation within the military; a loss of inhibition in viewing other human beings, including noncombatants, as resources for war, aided in part by the employment of scientific metaphors in the service of nationalistic ideologies; and scientists' self‐employment as resources for war efforts, accompanied by their attempts to use governments as resources for research projects that would not have been conceived, let alone funded, in peacetime. The essay concludes by outlining ways in which the following articles relate to these broader concerns.
Erinnern an die Gründung: Universitätsjubiläen, Universitätsgeschichte und die Entstehung der Jubiläumskultur in der frühen Neuzeit
Authors: Müller Winfried
Published: October 2006

The first part of the report pursues the development of the modern jubilee tradition. The ‘Holy Year’, introduced in 1300 by Pope Bonifaz VIII, and still being celebrated in a 25 years cycle since 1475 can be considered the root of this tradition. The Catholic monopoly of jubilees was then broken by some Protestant universities. Anniversary cycles were first performed by the universities of Tübingen (1578), Heidelberg (1587) and Wittenberg (1602) to commemorate the founding of the university by a secular sovereign. With the competition of confessions in the Reich in the background this adaption of the jubilee‐idea in the university area leads to a new religiously inspired jubilee tradition in the Protestant regional churches, which celebrated the anniversary of the Reformation regularly since 1617. To counteract the Protestant onslaught of jubilees the Roman jubilee‐year, planned for a universal church, changed in the outgoing 17th and 18th century to a historically based jubilee of the dioceses, monasteries and universities in Catholic regions. ‐ The guiding role of the universities in adopting and profaning the jubilee‐year led to an early concern with the institutions' own history.

As an early example for the rich production of jubilee books the anniversary speech of Heidelberg's deputy vice chancellor, Georg Sohn, of 1587 is introduced. Hence the close relationship between university jubilees and historical exploration of institutional, personal and academic history counts as a constant in university history, as will be seen in a second part with examples from the 19th and 20th century. Especially the university jubilees of the 1960s and 1970s contributed to a duration, and in parts even to the institutionalization of the historical partial discipline of the history of the universities. Finally, a few possible negative aspects of the close relationship of university jubilees to university historiography are being discussed.
Chemische Laboratorien: Funktion und Disposition
Authors: Meinel Christoph
Published: October 2006

In this essay laboratories are dealt with as symbolic spaces that structure social relationships and ways of knowledge in chemistry. The spatial vicissitudes of the nineteenth‐century research laboratory reflect, and at the same time direct, the way chemical knowledge is being produced, transmitted, and perceived.
Die Apotheke als Forschungsstätte
Authors: Dilg Peter
Published: October 2006

From the beginning, next to their essential function of preparing drugs pharmacies also served as educational institutions, in particular for the instruction of their own rising generation. Especially between 1750 and 1850 pharmacies in addition were engaged in scientific research. It were basically experimental‐analytic chemistry and after 1800 mainly phytochemistry which inspired numerous apothecaries to do corresponding work in their laboratories. For many of those scientifically ambitious pharmacists, however, pharmacies were merely a starting point in their professional career. More or less rapidly, they turned to other places of activity which were organizationally, socially, and intellectually of higher standards (e.g. academies or universities). There, they were better able to realize their research interests frequently roused and shaped in the pharmacies. When around 1850 chemistry as an autonomous discipline definitely was established at the universities and competition became increasingly apparent through the rising chemical industry, the former meaning and function of pharmacies as places of scientific research disappeared more and more and was completely lost about 1900.
Zytoarchitektonik und Revolution ‐ Lenins Gehirn als Raum und Objekt
Authors: Richter Jochen
Published: October 2006

The investigation of Lenin's brain by the German neurobiologist Oskar Vogt from Berlin and his Russian collaborators in Moscow is one of the most exciting and simultaneously oddest chapters in the history of medicine. With the bizarre claim to be able to detect the material substrate of genius it provoked as much unrealistic expectations in the public as strong criticism by the scientific community of brain researchers. The present paper deals in a brief survey with the history of collecting and measuring the brains of famous persons in general and particularly with the historical, political and social circumstances of the performed investigation of Lenin's brain. In this connection the epistemological and technical prereqisites of architectonical brain research and its means of the topographical representation of complex histo‐anatomical and physiological differences in the brain cortex are shortly discussed. The opening of Russian archives after the socio‐economic turn of the year 1991 brought up new background facts in Lenin's pathobiography; together with the sources from German archives a rather extensive reconstruction of the historical events between Lenin's death in 1924 and the final report of the Moscow Brain Research Institute (Institute Mozga) to the Politburo of the Russian Communist Party (Bolsheviki) in 1936 is possible now.
Der Natur‐Begriff des 17. Jahrhunderts und zwei seiner Inter‐pretamente: „res extensa”︁ und „intima rerum”︁
Authors: Leinkauf Thomas
Published: October 2006

This article aims to show the general and broad use of the concept of nature in the philosophical discourse of the 17th century ‐ and in this context it is obvious that this discourse includes both philosophy and theology. I will discuss two opposite views concerning its fundamental understanding of nature, yet will not go into elaborating differences concerning such particular concepts as, for example, space, void or motion. These views and the theoretical positions from which they emerged will here be called res extensa and intima rerum ‐ this is done in order to clarify the basic opposition: there is no interior in pure extension and there is no extension at all in that what is called the interior. My aim is to show that these two views are, in fact, not quite as incompatible and contradictory as it easily may seem at first glance. Although I will for heuristic purposes introduce the two concepts res extensa and intima rerum as complete opposites and in a wholly contrary manner, ist should become clear that there exist both influences and interactions between these two notions. Theorists introduced here as advocates of the intima rerum‐position, can, for example, be seen as having been influenced by the mechanistic, or res extensa‐position, mainly through the formally and methodologically attractive geometric and mathematical argumentation. Likewise theorists advocating a mechanistic position can be said at some points to have been led by a substantial necessity concerning the contect of their argumentation to take recourse to the concept of intima rerum, at least partly or in a modified manner.
Raumvorstellungen und Erkenntnismodelle im 18. Jahrhundert
Authors: Sandl Marcus
Published: October 2006

Since the late 17th century, two physical concepts of space exist. Isaac Newton's theory of an immovable ‘absolute space’ made it possible to explain motion and force by the quality of material elements. Less influential was Gottfried Wilhelm Leibniz's concept of space as an ‘order of coexistence’, which focuses, contrary to Newton, on the relationship between material bodies. The author argues that both concepts not only concern physical notions, but also include general models to explain cause, effect and relation. In an analogy to Newton's ‘absolute space’, theories of natural law employ the state of nature to explain society according to the anthropological quality of human beings. Leibniz's concept, in contrast, is used to elaborate theories of complex dynamic interactions and relationships. This essay attempts to illustrate the application of Leibniz's concept with examples of 18th century natural history, demography, economic theory and Charles Bonnet's natural law.
Synthesis and Crystal Structure of Pt2Sn2Zn3, the First Ternary Compound of the Pt/Sn/Zn System.
Authors: Lux Rainer , Hillebrecht Harald
Published: October 2006

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.
Cs2K2 [Pt12O8(SO4)12]: A New Oxide‐Sulfate with the Cluster Anion [Pt12O8(SO4)12]4‐.
Authors: Pley Martin , Wickleder Mathias S.
Published: October 2006

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF.