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beruecksichtige naturwissenschaftliche Journale:
Pharmaceutical Chemistry Journal - published by
Springer -
... is devoted to scientific and technical research on the creation of new drugs and the improvement of manufacturing technology of drugs and intermediates.
Archiv der Pharmazie, Chemistry in Life Sciences - published by
Wiley-Interscience -
... is an international journal devoted to research and development in all fields of pharmaceutical and medicinal chemistry.
Aktuelle wissenschaftliche Fachartikel der
genannten Journale:
A series of 2-substituted xanthone derivatives 8-20 containing selected allyl, cinnamyl, morpholine, and imidazole moieties were synthesized and tested for their antifungal and antibacterial in-vitro properties. Of the newly synthesized derivatives, ten revealed antifungal activity especially against Trichophyton mentagrophytes (the biggest inhibition zones ranged 35 mm for 11 and 13). 2-(3-(Allylamino)propoxy)-9H-xanthen-9-one hydrochloride 9 inhibited growth of all of the examined fungal species. Significant efficacy against evaluated yeasts and dermatophytes was also observed for 6-chloro-2-methyl-9H-xanthen-9-one derivatives 11-13 containing encyclic amine moieties. Additionally, compounds 9, 11, and 12 hindered development of bacteria species but in a lesser degree. They were efficacious against Staphylococcus aureus, Escherichia coli, and Enterococcus faecalis.
New N-(dimethylamino)ethyl derivatives of phthalazinones and pyridopyridazinones 7, 9 were synthesized and assayed as potential analgesic agents in the hot-plate, tail-flick, and writhing tests. Pharmacological assay demonstrated that eight (in ten) of the newly synthesized compounds showed antinociceptive activity. Especially, 2-[2-(dimethylamino)ethyl]-4-phenyl-2H-phthalazin-1-one 7a showed remarkably higher antinociceptive activity in all tests. This is connected with influence on supraspinal, spinal, and peripheral structures. The decreased sensitivity to the pain stimulus in the hot-plate was higher than that of metamizole.
In this study, we report the synthesis and antimicrobial evaluation of several new 4-(1H-benzimidazol-2-yl)benzamides (11-30) and 5-chloro-1-(p-fluorobenzyl)-2-{4-[(4-methylpiperazin-1-yl)carbonyl]phenyl}-1H-benzimidazole (33). Compound 20 exhibited the best antibacterial activity with MIC value of 6.25 [mu]g/mL against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus (MRSA). Significant antifungal activities were obtained with the compounds 13, 14, 18, 19, and 33 with MIC values of 3.12 [mu]g/mL which are close to fluconazole.
Nine title compounds were synthesized and investigated in the Born test for their antiplatelet activities against collagen, ADP, adrenaline, and platelet activating factor (PAF) as inducers of the aggregation. Using collagen three compounds with IC50 values below 100 [mu]M were found (3b, 3e, 3i). Activities in nanomolar concentrations were observed against ADP (3b, IC50 = 9.4 nM), adrenaline (3i, IC50 = 5.8 nM), and platelet activating factor (3e, IC50 = 0.45 nM).
Analysis of pyracetam in available parent powders using differential scanning calorimetry (DSC) showed that there are at least
two main polymorphic forms of pyracetam on the pharmaceutical market. One of these is converted into the other during heating
and storage. Two polymorphic forms of pyracetam have been found in pyracetam capsules, in contrast to tablets where only one
form is present. The results show that amorphization of crystalline active ingredient during heating of dosed forms including
polyethyleneglycol or other carriers should be taken into account during analysis by means of DSC.
Content Type Journal Article
DOI 10.1007/s11094-008-0143-5
Authors
A. V. Titova, Ministry of Public Health of the Russian Federation Institute for Drug Standardization, State Scientific Center for Drug Review and Control Moscow Russia
A. P. Arzamastsev, Sechenov Medical Academy Moscow Russia
D. Yu. Chashkin, Ministry of Public Health of the Russian Federation Institute for Drug Standardization, State Scientific Center for Drug Review and Control Moscow Russia
The reactions of 4-(aminobenzenesulfonamide)-2-thiazole with the appropriate 8-benzodioxane aldehydes were used to synthesize
a series of new azoethines. The proposed structures are confirmed by IR and NMR spectroscopy. It is shown that the obtained
azomethines exhibit high (97–100%) activity against Mycobacterium tuberculosis H37Rv at a concentration of 0.2–1.5 mg-mL in vitro.
Content Type Journal Article
Category Search for New Drugs
DOI 10.1007/s11094-008-0135-5
Authors
R. T. Tlegenov, Berdakh Karakalpak State University Nukus Karakalpak Republic Uzbekistan
Chromatographic micro-preparative separation of a racemic mixture of naproxen enantiomers using a chiral stationary phase
of Chiralcel OJ-H has been studied. Optimum conditions for the separation have been found. It is shown that a special fraction
collection scheme involving an intermediate region between the minimum between peaks and the maximum of the second peak should
be used for the simultaneous recovery of both enantiomers. In this case, S-(0.12 mg) and R-naproxen (0.12 mg) with a purity of up to 99.4 and 94.5%, respectively, can be isolated in one run using a standard analytical
column.
Content Type Journal Article
DOI 10.1007/s11094-008-0145-3
Authors
L. D. Asnin, Russian Academy of Sciences Institute of Technical Chemistry, Ural Branch Perm Russia
The near infrared range (NIR) of the electromagnetic spectrum extends from 800 to 2500 nm, being confined between the middle
IR and visible spectral regions. The method of NIR spectroscopy is based on a combination of spectrophotometry and statistical
methods of multifactor analysis, which provides excellent possibilities for drug identification and quality control even without
opening the package. We have studied a series of drugs including cefazolin sodium and generic drugs based on enalapril maleate.
True and falsified variants of a given drug X were classified into groups according to “drug name,” “drug manufacturer,” and
“falsified product” by means of NIR spectroscopic analyses performed using the NIR Fourier-transform instruments Multi Purpose
Analyzer (Bruker, Germany) and Antaris (Thermo Electron Corporation, USA). The potential of this method for the identification
of drugs without violation of their packing shows good prospects for introducing it into the drug quality control system.
This method should be recommended for introduction into the future Russian State Pharmacopoeia as a general method of drug
analysis.
Content Type Journal Article
DOI 10.1007/s11094-008-0146-2
Authors
T. E. Elizarova, FARMANALIZ Analytical Control Laboratory Moscow Russia
S. V. Shtyleva, FARMANALIZ Analytical Control Laboratory Moscow Russia
T. V. Pleteneva, Peoples Friendship University Medical Faculty Moscow Russia
The antitumor properties of 2-imidazolinyl-2-hydrazones of acetophenones with various substituents in the benzene ring have
been studied. High activity is found for 4-amyloxy-3-nitroacetophenone 2-imidazolinyl-2-hydrazone, which points to the expediency
of its further investigation.
Content Type Journal Article
DOI 10.1007/s11094-008-0133-7
Authors
M. A. Iradyan, National Academy of Sciences of Armenia Mndzhoyan Institute of Fine Organic Chemistry Yerevan Armenia
R. A. Aroyan, National Academy of Sciences of Armenia Mndzhoyan Institute of Fine Organic Chemistry Yerevan Armenia
G. M. Stepanyan, National Academy of Sciences of Armenia Mndzhoyan Institute of Fine Organic Chemistry Yerevan Armenia
F. G. Arsenyan, National Academy of Sciences of Armenia Mndzhoyan Institute of Fine Organic Chemistry Yerevan Armenia
B. T. Garibdzhanyan, National Academy of Sciences of Armenia Mndzhoyan Institute of Fine Organic Chemistry Yerevan Armenia
Extended-release primaquine tablets were developed using polyethylene oxide (PEO) as a hydrophilic swellable polymer with
different amounts and molecular weights (4 × 106 and 8 × 106). Investigations were carried out in order to verify the matrix performance. The evaluated parameters were weight, hardness,
thickness, friability, and drug content. The swelling and erosion matrices as well as drug release profile were analyzed under
dissolution conditions. The statistical model ANOVA and Tukey-Kramer HSD were considered. The results showed that all formulations
provided adequate physical characteristics and a time release about eight hours following a non-Fickian diffusion model. The
kinetics of drug delivery was directly related to the synchronization of swelling and erosion matrices. The formulations prepared
with high PEO concentrations showed a lower rate of erosion, a slower drug release, and faster rate of swelling, as compared
with matrices containing lower PEO concentration.
Content Type Journal Article
DOI 10.1007/s11094-008-0137-3
Authors
A. P. Cruz, Universidade Federal de Santa Catarina Departament of Pharmaceutical Sciencs Florianópolis SC Brazil
C. D. Bertol, Universidade Federal de Santa Catarina Departament of Pharmaceutical Sciencs Florianópolis SC Brazil
H. K. Stulzer, Universidade Federal de Santa Catarina Departament of Pharmaceutical Sciencs Florianópolis SC Brazil
F. S. Murakami, Universidade Federal de Santa Catarina Departament of Pharmaceutical Sciencs Florianópolis SC Brazil
F. T. Costella, Universidade Federal de Santa Catarina Departament of Pharmaceutical Sciencs Florianópolis SC Brazil
H. V. A. Rocha, Fundação Oswaldo Cruz, Fiocruz Departament of Pharmaceutical Technology Rio de Janeiro RJ Brazil
M. A. S. Silva, Universidade Federal de Santa Catarina Departament of Pharmaceutical Sciencs Florianópolis SC Brazil
Adsorptive stripping Voltammetric determination of irbesartan using a hanging mercury drop electrode (HMDE) is described.
The method is based on adsorptive accumulation of the species at the HMDE, followed by a first-harmonic alternating current
(AC) stripping sweep at pH 6. The behavior of the adsorptive stripping response was studied under various experimental conditions,
e.g., type of supporting electrolyte, pH, accumulation time, scan rate, and mode of sweep. In Britton-Robinson buffer solution,
a quasi-reversible reduction process involving transfer of two electrons and two protons takes place. The response was linear
over the concentration range of 0.16–1.60 µg/ml with regression coefficient 0.997 and detection limit 0.11 µg/ml. The average
of determinations of the cited compound in oral dosages with its standard deviation was 99.39 ± 4.33 %.The result obtained
by the proposed method was compared with that obtained by the uv-spectrophotometric technique. Furthermore, the proposed method
was also successfully applied as a stability-indicating method.
Content Type Journal Article
DOI 10.1007/s11094-008-0144-4
Authors
I. H. I. Habib, National Research Centre, Dokki Applied Organic Chem. Dept. Cairo Egypt
S. A. Weshahy, Cairo University Anal. Chem. Dept., Faculty of Pharmacy Cairo Egypt
S. Toubar
M. M. A. El-Alamin, Helwan University Anal. Chem. Dept., Faculty of Pharmacy Cairo Egypt
The acid-neutralizing properties of widely used antacid preparations and the new experimental tablets Antacid-1 and Antacid-2
containing activated charcoal were compared in vitro. It is established that the new medicinal antacids differ from the well-known analogs by a greater acid-neutralizing capacity
and a higher rate of hydrochloric acid neutralization.
Content Type Journal Article
DOI 10.1007/s11094-008-0139-1
Authors
D. D. Grinshpan, Belarus State University Research Institute for Physico-Chemical Problems Minsk Belarus
T. N. Nevar, Belarus State University Research Institute for Physico-Chemical Problems Minsk Belarus
T. A. Savitskaya, Belarus State University Minsk Belarus
A. V. Boiko, Belarus State University Minsk Belarus
N. V. Kapralov, Belarus State Medical University Minsk Belarus
I. A. Sholomitskaya, Belarus State Medical University Minsk Belarus
Determination of the content of vitamin D is a rather difficult problem. In the present study, we have compared methods that
are most widely used for determining group D vitains. In recent years, physical and chemical methods of analysis have found
increasing use due to their simplicity, sensitivity, and information value. Various methods of quality control are currently
used but the future in the analysis of calciferols undoubtedly belongs to HPLC. This method is capable of simultaneously solving
all problems encountered in the analysis of group D vitamins.
Content Type Journal Article
Category Structure of Chemical Compounds, Methods of Analysis and Process Control
DOI 10.1007/s11094-008-0140-8
Authors
O. V. Rybakova, Voronezh State University Novonezh Russia
E. F. Safonova, Voronezh State University Novonezh Russia
A. I. Slivkin, Voronezh State University Novonezh Russia
Reaction of 4-aryl-2-hydroxy-4-oxo-2-butenoic acid N-hetarylamides with copper, zinc, and cadmium dichlorides led to the formation of bis[3-aryl-1-(N-hetaryl)carboxamido-1,3-propanedionato]copper,-zinc, and-cadmium, respectively. Compounds with high antimicrobial activity
were found among these products.
Content Type Journal Article
DOI 10.1007/s11094-008-0147-1
Authors
N. A. Pulina, Perm State Pharmaceutical Academy Perm Russia
P. A. Mokin, Perm State Pharmaceutical Academy Perm Russia
V. V. Yushkov, Perm State Pharmaceutical Academy Perm Russia
V. V. Zalesov, Perm State University Perm Russia
T. F. Odegova, Perm State Pharmaceutical Academy Perm Russia
M. V. Tomilov, Perm State Pharmaceutical Academy Perm Russia
K. V. Yatsenko, Perm State Pharmaceutical Academy Perm Russia
A method for evaluating mucoadhesive properties of polymer films that employs a model mucosa and wetting of tissues imitating
physiological conditions is proposed. The results show evidence for good mucoadhesive properties of natural biocompatible
polymers such as alginate and chitosan. The proposed method can be used to compare the mucoadhesive strength of various polymers
widely used in pharmaceutical technology.
Content Type Journal Article
DOI 10.1007/s11094-008-0132-8
Authors
E. A. Kharenko, Sechenov Moscow Medical Academy Department of Pharmacy 119881 Moscow Russia
N. I. Larionova, Moscow State University Department of Chemistry 119992 Moscow Russia
N. B. Demina, Sechenov Moscow Medical Academy Department of Pharmacy 119881 Moscow Russia
A state of pre-adaptation to highly toxic doses of sulfuryl derivatives of benzimidazole and benzotriazole was developed in
Staphylococcus aureus species by treating them with non-toxic doses of these compounds. Pre-treatment of S. aureus with the starting benzazolides (benzimidazole and benzotriazole) also created the pre-adaptation to their sulfuryl derivatives.
Experiments on cross-pre-adaptation where the pre-adaptation to sulfuryl derivatives of benzazolides was created by the action
of non-toxic doses of benzotriazole and vice versa showed that the planar structures of the double ring of benzazolide plays
a key role in activation of the repair systems of S. aureus. Mathematical analysis revealed a high nonlinear correlation between the ability of a compound to create the state of pre-adaptation
in S. aureus culture on one hand and the physical and chemical properties such as the lipophilicity, molecular weight and volume, and
hydration energy on the other.
Content Type Journal Article
Category Molecular-Biological Problems of Drug Design and Mechanism of Drug Action
DOI 10.1007/s11094-008-0136-4
Authors
E. S. Selezneva, Samara State University Samara Russia
E. I. Ten’gaev, Samara State University Samara Russia
Chlorides of 2-arylaminocinchoninic acid pyridinioacetylhydrazides were synthesized via interaction of the chloroacetylhydrazides
of these acids with pyridine and its derivatives. These compounds showed antimicrobial activity and influenced blood coagulation.
Content Type Journal Article
DOI 10.1007/s11094-008-0134-6
Authors
M. E. Kon’shin, Perm State Pharmaceutical Academy Perm Russia
B. Ya. Syropyatov, Perm State Pharmaceutical Academy Perm Russia
A. L. Efremov, Perm State Pharmaceutical Academy Perm Russia
T. F. Odegova, Perm State Pharmaceutical Academy Perm Russia
M. M. Vakhrin, Perm State Pharmaceutical Academy Perm Russia
The antibacterial activity in vitro and in vivo and the toxicity of Lidoxycol ointment, which is a new medicinal form of dioxidine, have been studied in comparison to the
properties of Dioxycol ointment. The results showed that Lidoxycol is identical to Dioxycol with respect to the spectrum of
antimicrobial action, chemotherapeutic efficiency, and tolerance.
Content Type Journal Article
DOI 10.1007/s11094-008-0141-7
Authors
T. V. Pushkina, All-Russia Research Institute of Pharmaceutical Chemistry Center for Drug Chemistry Moscow Russia
L. Yu. Krylova, All-Russia Research Institute of Pharmaceutical Chemistry Center for Drug Chemistry Moscow Russia
S. A. Sharova, All-Russia Research Institute of Pharmaceutical Chemistry Center for Drug Chemistry Moscow Russia
L. A. Chicherina, All-Russia Research Institute of Pharmaceutical Chemistry Center for Drug Chemistry Moscow Russia
O. S. Kuzina, All-Russia Research Institute of Pharmaceutical Chemistry Center for Drug Chemistry Moscow Russia
Conditions have been chosen for the decomposition of yttrium orthotantalate and the subsequent determination of yttrium and
tantalum in this compound, which is used as an x-ray contrast agent. Methods are developed for the identification of yttrium
and tantalum using complexation reactions. These methods have proven to be specific and can be recommended for the identification
of yttrium and tantalum in the new preparation of yttrium orthotantalate 3% suspension for use in x-ray fluorography. Infrared
spectroscopy can be used to confirm the identity of yttrium orthotantalate in the studied pharmacological agent.
Content Type Journal Article
DOI 10.1007/s11094-008-0142-6
Authors
E. A. Mamashina, State Scientific Center for Drug Review and Control Institute for Drug Standardization Moscow Russia
T. N. Bokovikova, State Scientific Center for Drug Review and Control Institute for Drug Standardization Moscow Russia
E. P. Gernikova, State Scientific Center for Drug Review and Control Institute for Drug Standardization Moscow Russia
A comparative study of the adsorption activity of some medical sorbents with respect to physiologically active substances
with different molecular weights has been carrried out. It is shown that Siliks (Polysorb MP) exhibits greater ability to
adsorb proteins in comparison to other sorbents. In contrast, the carbon-based sorbents do not absorb proteins but have a
high affinity for low-and medium-molecular-weight substances. The adsorption activity of Smecta in acid media is close to
that of carbons. Due to similar chemical properties, the Siliks and Enterosgel preparations demonstrate analogous adsorption
characteristics.
Content Type Journal Article
DOI 10.1007/s11094-008-0138-2
Authors
D. A. Markelov, A. A. Bogomolets National Medical University Kiev Ukraine
O. V. Nitsak, A. A. Bogomolets National Medical University Kiev Ukraine
I. I. Gerashchenko, National Academy of Sciences of Ukraine Institute of Surface Chemistry Kiev Ukraine
A series of [omega]-aminoalkoxylxanthones was synthesized and tested in vitro for their ability to inhibit platelet aggregation and cause vasorelaxing action. Compounds 4, 5, 12, 17, and 18 showed significant antiplatelet effects on thrombin-, arachidonic acid (AA)-, collagen-, and platelet activating factor (PAF)-induced washed rabbit platelet aggregation and exhibited inhibition of primary and secondary aggregation induced by adenosine-5'-diphosphate (ADP) in human platelet-rich-plasma (PRP). Compounds 4, 17, and 18 revealed vasorelaxing activities in rat thoracic aorta. We concluded that these compounds may be developed as new antithrombotic agents.
A series of novel thiourea derivatives carrying the 5-cylohexylamino-1,3,4-thiadiazole moiety was synthesized and their anticonvulsant activity was evaluated. Structures of the synthesized compounds have been confirmed by IR, 1H-NMR, and elemental analysis. All of the compounds were administered at a dose of 50 mg/kg. Some of the active compounds have different effects in pentylenetetrazole (PTZ) and maximal electroshock (MES) tests, indicating the therapeutical potential in petit mal seizures, but not in grand mal seizures. Compounds 10, 11, 13, and 14 carrying 2-methylphenyl, 4-chlorophenyl, allyl, and 4-methylphenyl on the thiourea pharmacophore, increased the survival rate in the PTZ model. The ED50 values of the active compounds 10, 11, 13, and 14 were found 68.42, 43.75, 18.75 and 25 mg/kg, respectively.
Abstract Indane-1,3-dione (1) synthesized by condensation of diethyl phthalate and ethyl acetate in the presence of sodium ethoxide
gave the sodium salt of the ester derivative, which on neutralization in the presence of sulfuric acid afford 1. Various thiols were converted to disulfide (3) which on treatment with 1 gave 2-substituted thiophenyl derivatives (4a–g) of 1. The synthesized compounds were characterized on the basis of IR and 1H NMR. The synthesized compounds (4a–g) were investigated for their anticoagulant, analgesic, anti-inflammatory, antifungal, antibacterial, and anticancer activities.
Some of the synthesized compounds have shown moderate activities.
Content Type Journal Article
DOI 10.1007/s11094-008-0120-z
Authors
D. Giles, K. M. College of Pharmacy Madurai India
M. S. Prakash, K. M. College of Pharmacy Madurai India
K. V. Ramseshu, K. M. College of Pharmacy Madurai India
Abstract The antianemic activity of water-soluble polymetallocomplexes of pectin polysaccharides containing d metal ions — Fe2+, Co2+, and Cu2+ — at different ratios was studied in laboratory rats. The results showed that complexes had marked stimulatory effects on
hematopoietic processes, with increases in hemoglobin concentrations and erythrocyte counts, along with intensification of
the recovery of hematological parameters after anemia induced by hemorrhage. The highest level of activity on hematological
measures was obtained with the polymetallocomplex containing Fe2+, Co2+, and Cu2+ ions at a ratio close to 1:1:1.
Content Type Journal Article
Category The Search for New Therapeutic Substances
DOI 10.1007/s11094-008-0130-x
Authors
A. B. Vyshtakalyuk, A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Russia
A. N. Karaseva, A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Russia
V. V. Karlin, A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Russia
S. T. Minzanova, A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Russia
V. F. Mironov, A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Russia
A. I. Konovalov, A. E. Arbuzov Institute of Organic and Physical Chemistry Kazan Russia
Abstract Aseries of copper (II) streptocide-, sulfacyl-, norsulfazole-, ethazole-, and sulfadimezine-containing naphthalidenethiosemicarbazidates
and napthalidene-4-phenylthiosemicarbazidates with high levels of antimicrobial activity were synthesized. Elemental analysis,
magnetochemical, IR spectroscopic, and thermogravimetric data were used to confirm the compositions and structures of the
resulting complexes. The effects of the nature of the central atom and the influences of the sulfanilamide and phenyl radicals
in the azomethine thiosemicarbazone fragment on the antimicrobial activity of the compounds against 10 strains of Gram positive
and Gram negative microorganisms were studied. The most active of the compounds synthesized were the copper norsulfazole-,
ethazole-, and sulfadimezine-containing naphthalidenethiosemicarbazidates.
Content Type Journal Article
DOI 10.1007/s11094-008-0118-6
Authors
A. P. Gulya, Moldova State University Kishinev Moldova
V. I. Prisakar, N. Testemitsan State University of Medicine and Pharmacy Kishinev Moldova
V. I. Tsapkov, Moldova State University Kishinev Moldova
S. A. Buracheva, N. Testemitsan State University of Medicine and Pharmacy Kishinev Moldova
S. N. Spynu, Moldova State University Kishinev Moldova
N. P. Bezhenar, Moldova State University Kishinev Moldova
Abstract 4,6-Dimethoxyhomophthalic acid (5) has been synthesized efficiently in four steps from 3,5-dimethoxycinnamic acid (1) and characterized and screened for their in vitro antibacterial activity against four Gram negative (Escherichia coli, Pseudomonas aeruginosa, Salmonella typhii, and Shigella flexneri) and two Gram-positive (Bacillus subtilis and Staphylococcus aureus) bacterial strains, and for in vitro antifungal activity against Trichophyton longifusus, Candida albicans, Aspergillus flavus, Microsporum canis, Fusarium solani, and Candida glaberata. The compounds were screened for their in vitro antiherbicidal and antifungicidal activities.
Content Type Journal Article
DOI 10.1007/s11094-008-0121-y
Authors
Ghulam Qadeer, Quaid-I-Azam University Department of Chemistry Islamabad 45320 Pakistan
Nasim Hasan Rama, Quaid-I-Azam University Department of Chemistry Islamabad 45320 Pakistan
Muhammad Zareef, Quaid-I-Azam University Department of Chemistry Islamabad 45320 Pakistan
Najim A. Al-Masoudi, Universität Konstanz Formerly Fachbereich Chemie Postfach 5560, M-655 D-78457 Konstanz Germany
