Syntheses and odor of "bulky group"-modified sandalwood odorants: isophorono-beta-santalol analogues.

Three osmophoric points have been found to be necessary for the scent of sandalwood odorants. One of these points is the bulky group in a certain distance from the osmophoric hydroxyl group. Such a hydrophobic moiety is part of the trimethylcyclopentenyl derivatives, the so called campholenals, among them many are known to exert a strong and long lasting sandalwood odor. In continuation of our SAR-studies of sandalwood odorants four isophorone analogues of beta-santalol have been synthesized. The hydrophobic region of these new isophorone derivatives is now a trimethylcyclohexene nucleus, so to speak an extension of the cyclopentene part of the campholenals by one methylene group. This modification changes the sandalwood odor drastically to woody odor notes, reminiscent only to sandalwood odor. The environs of the crowded trimethylcyclohexene nucleus demonstrate the sensitivity of sandalwood odor on the shape of the hydrophobic, bulky part of beta-santalol analogues.

Synthesis and complete 1H, 13C and 15N NMR assignment of substituted isoxazolo[3,4-d]pyridazin-7(6H)-ones.

The synthesis and complete assignment of all hydrogen, carbon and nitrogen NMR signals of several new isoxazolo[3,4-d]pyridazin-7(6H)-ones is reported. The spectroscopic characterization is extended to previously described analogues.

Spectroscopic characterization of flavin mononucleotide bound to the LOV1 domain of Phot1 from Chlamydomonas reinhardtii.

The absorption and emission behavior of flavin mononucleotide (FMN) in the light-, oxygen- and voltage-sensitive (LOV) domain LOV1 of the photoreceptor Phot1 from the green alga Chlamydomonas reinhardtii was studied. The results from the wild-type (LOV1-WT) were compared with those from a mutant in which cysteine 57 was replaced by serine (LOV1-C57S), and with free FMN in aqueous solution. A fluorescence quantum yield of phi(F) = 0.30 and a fluorescence lifetime of tau(F) = 4.6 ns were determined for FMN in the mutant LOV1-C57S, whereas these quantities are reduced to about phi(F) = 0.17 and tau(F) = 2.9 ns for LOV1-WT, indicating an enhanced intersystem crossing in LOV1-WT because of the adjacent sulfur of C57. A single-exponential fluorescence decay was observed in picosecond laser time-resolved fluorescence measurements for both LOV1-WT and LOV1-C57S as expected for excited singlet state relaxation by intersystem crossing and internal conversion. An excitation intensity dependent fluorescence signal saturation was observed in steady-state fluorescence measurements for LOV1-WT, which is thought to be because of the formation of a long-lived intermediate flavin-C(4a)-cysteinyl adduct in the triplet state (few microseconds triplet lifetime, adduct lifetime around 150 s). No photobleaching was observed for LOV1-C57S, because no thiol group is present in the vicinity of FMN for an adduct formation.

Synthesis, cytotoxicity, and antitumor activity of copper(II) and iron(II) complexes of (4)N-azabicyclo[3.2.2]nonane thiosemicarbazones derived from acyl diazines.

A series of thiosemicarbazones (TSCs) (bearing a (4)N-azabicyclo[3.2.2]nonane moiety) derived from 3-acylpyridazines, 4-acetylpyrimidines, and 2-acetylpyrazines (1-8) were synthesized as potential antitumor agents. TSCs 1-8 exhibited potent cytotoxic activity against human acute lymphoblastic leukemia CCRF-CEM cells (IC(50) = 0.05-0.77 microM) and colon adenocarcinoma HT-29 cells (IC(50) = 0.011-2.22 microM). Copper II complexes of TSCs 1-8 showed significant improvement in cytotoxic activity against HT-29 cells (IC(50) = 0.004-1.51 microM) by a factor of 3. However, complexation of ligands 1, 2, 4, and 6 with Fe(II) results in lowering of cytotoxic activity by a factor of approximately 7. In clonogenic assays involving human tumor cells of different tumor origins, compounds 5, 7, 8, and their copper complexes 5Cu(II), 7Cu(II), and 8Cu(II) exhibited remarkable cytotoxic activities with mean IC(50) values of 6, 0.18, 1, 1, 0.37, and 0.37 nM, respectively. In particular, the compounds were highly effective against human colon carcinoma and large and small cell lung carcinoma cells. The TSC derivative 5 was evaluated in vivo in nude mice bearing LXFL 529 human large cell lung carcinoma cells. With respect to antitumor activity, application of 30 mg/kg/d resulted in moderate inhibition (42%) of tumor growth. No effect on tumor growth was observed at a dose of 10 mg/kg/d. However, a dose of 40 or 60 mg/kg/d resulted in 50 and 75% death, respectively, in the treated mice, indicating the high toxicity of these compounds. Using human liver microsomes, compound 5 was found to be rapidly and highly metabolized in vitro. In actual fact, only 2% of the unmetabolized compound could be detected in the incubation medium after 5 min. The IC(50) for cell proliferation (0.006-0.022 microM) elicited by these compounds is much lower than that of the inhibition of [(14)C]cytidine incorporation into DNA (0.18-3.32 microM). These compounds are also noncell cycle specific agents. Interestingly, compounds 5, 5Cu(II), and 8 were found to be potent inducers of apoptosis in Burkitt's lymphoma cells.

Serum bile acids in captive bustards.

Blood samples were collected from clinically normal male and female houbara (Chlamydotis undulata macqueenii), kori (Ardeotis kori), buff-crested (Eupodotis ruficrista gindiana) and white-bellied bustards (E. senegalensis) to determine serum bile acid concentrations. Bile acid concentrations were determined by analysis with an Ultrospec 3000 ultraviolet/visible spectrophotometer, using an enzymatic bile acid test. The results provided values of serum bile acid concentrations for the four species, with means +/- standard errors of 35.8 +/- 2.8 mumol; 51.1 +/- 5.0 mumol; 18.4 +/- 2.1 mumol and 20.8 +/- 5.4 mumol for the houbara, kori, buff-crested and white-bellied bustard, respectively. Although no gender or age differences were detected within species, the results demonstrated significant differences in concentrations in clinically normal individuals between the different species.

Synthesis, spectral and antimicrobial properties of 5-chloroarylidene aromatic derivatives of imidazoline-4-one.

The synthesis of new chloro-benzylidene substituted derivatives of hydantoin and their antimicrobial activity is reported. The structure-activity relationships showed that the antibacterial effect of investigated compounds depends on the distance of the phenyl ring from the amine residue and the kind of substitutes on the phenyl ring. In the investigated group of derivatives, 5-(2-chlorobenzylidene)-2-(4-fluorobenzylamine)-imidazoline-4-one and 5-(2-chlorobenzylidene)-2-(2-phenylethylamine)-imidazoline-4-one showed the best antibacterial activity against Moraxella catarrhalis.

Substituted 4-acylpyrazoles and 4-acylpyrazolones: synthesis and multidrug resistance-modulating activity.

A series of 4-acyl-3-pyrazolone derivatives with a 3-substituted 2-hydroxy-3-aminopropyl chain attached to pyrazole N-1 (7-20) as well as isomeric 4-acyl-5-(3-substituted 3-amino-2-hydroxypropoxy)pyrazole derivatives (5, 6) were synthesized, and their multidrug resistance (MDR)-modulating activity was measured using the daunomycin efflux assay. Reaction of N1-substituted 4-acyl-3-pyrazolones (tautomer to 4-acyl-5-hydroxypyrazoles) with excessive epichlorohydrin and successive treatment with an appropriate amine resulted in N-alkylation and thus afforded the target pyrazolone derivatives 7-20. In contrast, O-alkylation occurred upon reaction with 1 equiv of epichlorohydrin and subsequent treatment with amine leading to the corresponding 4-acyl-5-pyrazolyl ethers 5 and 6. QSAR studies showed a good correlation of MDR-modulating activity with lipophilicity of the compounds. Inclusion of hydrogen bond acceptor strength and steric parameters as descriptors led to a QSAR equation with remarkably increased predictive power (r2cv = 0.92). Additionally, ortho substitution of the propanolamine side chain and the acyl moiety is favorable. Detailed NMR spectroscopic investigations were carried out with the title compounds.

Potent enzyme inhibitors derived from dromedary heavy-chain antibodies.

Evidence is provided that dromedary heavy-chain antibodies, in vivo-matured in the absence of light chains, are a unique source of inhibitory antibodies. After immunization of a dromedary with bovine erythrocyte carbonic anhydrase and porcine pancreatic alpha-amylase, it was demonstrated that a considerable amount of heavy-chain antibodies, acting as true competitive inhibitors, circulate in the bloodstream. In contrast, the conventional antibodies apparently do not interact with the enzyme's active site. Next we illustrated that peripheral blood lymphocytes are suitable for one-step cloning of the variable domain fragments in a phage-display vector. By bio-panning, several antigen-specific single-domain fragments are readily isolated for both enzymes. In addition we show that among those isolated fragments active site binders are well represented. When produced as recombinant protein in Escherichia coli, these active site binders appear to be potent enzyme inhibitors when tested in chromogenic assays. The low complexity of the antigen-binding site of these single-domain antibodies composed of only three loops could be valuable for designing smaller synthetic inhibitors.

Photostability and thermal stability of indocyanine green.

The photo-fading of the S0-S1 absorption band of the infrared dye indocyanine green sodium iodide (ICG-NaI) has been studied by cw laser excitation to the S1 band. Monomeric solutions in water, heavy water, aqueous sodium azide, human plasma, methanol and dimethyl sulfoxide (DMSO) as well as J-aggregated solutions in H2O and D2O have been investigated. A leucoform of indocyanine green seems to be formed by photodegradation. The degradation slows down with exposure time. The initial degradation yield, phi D,0, is determined. In monomeric and dimeric water, heavy water and sodium azide solutions the initial photostability is of the order of phi D.0 approximately 10(-3), in the organic solvents methanol and DMSO it is of the order of phi D.0 approximately 10(-5), and in human plasma it is phi D.0 approximately 2 x 10(-6). J-aggregates at high concentration are very stable. The thermal stability of the ICG-NaI solutions at room temperature in the dark is compared with their photostability. The thermal degradation time of monomeric and dimeric ICG-NaI in water, heavy water and sodium azide solutions is t(th) approximately 10 days, while no thermal degradation is observed for ICG-NaI J-aggregates and ICG-NaI in methanol, DMSO and human plasma.

On the bioisosteric potential of diazines: diazine analogues of the combined thromboxane A2 receptor antagonist and synthetase inhibitor Ridogrel.

In this SAR study the bioisosteric potential of diazines in the field of combined antithrombotic thromboxane A2 synthetase inhibitors and receptor antagonists was investigated. In this context, two series of (E)- and (Z)-omega-[[(aryldiazinylmethylene)amino]oxy]alkanoic acids were synthesized of which pentanoic acid derivatives with a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl group were found to exhibit this dual activity, while 4-pyrimidinyl as well as 3-pyridazinyl analogues showed only receptor antagonistic activity and 2-pyrimidinyl congeners were inactive. In the series of diazine analogues of Ridogrel (1), replacement of the 3-pyridyl group by a 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl moiety led to compounds that inhibit thromboxane A2 synthetase in gel-filtered human platelets comparable to 1 (IC50 of 0.006, 0.016, and 0.039 microM, respectively, versus 0.007 microM). Radioligand-binding studies with [3H]SQ 29,548 in washed human platelets revealed that these diazine analogues block the thromboxane A2 receptor with an IC50 of 11, 6.0, and 1.5 microM, respectively. This compares well with the IC50 = 1.7 microM of 1. Finally, testing of inhibition of collagen-induced platelet aggregation in human platelet aggregation in human platelet-rich plasma with 2-pyrazinyl, 4-pyridazinyl, or 5-pyrimidinyl congeners of Ridogrel indicated that these heteroaromatic moieties may serve as bioisosteric substitutes of a 3-pyridyl group in dual-acting antiplatelet agents.

A fusion protein of IL-8 and a Fab antibody fragments binds to IL-8 receptors and induces neutrophil activation.

A fusion protein was generated by genetic engineering which combined a Fab fragment of a monoclonal antibody directed to the human epidermal growth factor receptor with the biologically active N-terminally truncated 2-72 amino acid form of the human chemokine IL-8. The Fab IL-8 fusion protein was expressed in E. coli and antibody binding and IL-8 activity were determined. Our data indicate that the N-terminus of IL-8 remains functional for receptor interaction. The fusion protein showed specific binding to IL-8 receptors, induced IL-8 mediated chemotactic activity, and the release of MPO activity. However, N-terminal fusion of IL-8 to the carboxyl terminus of the Fab fragment resulted in reduced binding to IL-8 receptors and consequently to reduced biologic activity of IL-8. The affinity of the antibody arm for EGF-R was improved when compared to a monovalent Fab. Fusion proteins as described herein may represent improved therapeutics for cancer therapy based on their potential to selectively increase and prolong cytokine concentration in the tumour. Since chemokines such as IL-8 recruit effector cells and stimulate effector cell function in situ, a lymphocyte-independent anti-tumour activity followed by tumour-specific immunity could be proposed.

On the synthesis of pyridazomycin congeners. Part 2: L-alpha-Amino acids bearing a terminal azinium or diazinium system.

The synthesis of a variety of novel compounds structurally related to the antimicrobial natural product pyridazomycin via alkylation of appropriate azine and diazine derivatives is reported. Based on the results of preliminary antimicrobial tests the dependence of antimicrobial activity from several structural features of pyridazomycin is discussed.

Pyridazines, LXXII: On the synthesis of azinium and diazinium compounds structurally related to pyridazomycin.

Preparation of series of pyridine-, pyridazine-, and pyrazine-derived carboxamides bearing at the ring N-atom an alkyl side-chain with a terminal carboxylic group (7-11) or with a terminal acetylamino malonic ester moiety (13-17, 19-23) is described. Two desaza-pyridazomycin derivatives (24, 26) and homologs thereof (25, 27) were synthesised. The novel compounds which are structurally related to the antifungal antibiotic pyridazomycin were screened for antifungal activity: preliminary in vitro tests showed no activity.

[Xenophobia in Austria? Attitudes toward migration, foreign population, and the state's policy on foreigners]. / Fremdenfeindlichkeit in Osterreich? Einstellungen zu Migration, auslandischer Bevolkerung und staatlicher Auslanderpolitik.

PIP: "At present some 700,000 foreigners (almost 9% of the total population) are living in Austria, about 280,000 of which are in the labor market. A representative sample of Austrians between 20 and 54 years [of age] were asked about their attitudes toward foreign population and migration policy." The findings indicate that various degrees of higher tolerance were correlated with being young, male, urban, living in a province with a high foreign population, and high socioeconomic status. "Stepping up the integration of the foreign population...is supported by a minority of Austrians only; as for the education of the children of immigrants, the Austrian attitude is a more generous one." (EXCERPT)^ieng

[Desired family size, actual family size, and family policies in Austria]. / Kinderwunsch, Kinderzahl und Familienpolitik in Osterreich.

PIP: "The demographic trend of decreasing numbers of children and the rising share of elderly prevailing in most industrialized countries is considered a problem by a large part of the Austrian population. Marriage and family continue to be of central importance.... These are results of the Austrian Population Policy Acceptance Survey (PPA) carried out in 1993. On the average, Austrians born between 1953 and 1972 want 1.99 children, which is clearly above the present (1995) total fertility rate of 1.40....[They] expect the government to assume the main responsibility for family and social matters. 40 percent of the Austrians consider the government fully responsible for helping women to manage child raising and jobs. Only one third of the population are fully content with family [policies], and some 40 percent consider social benefits for families not sufficiently generous.... The effects family [policy] measures have on the desire to have children and its realization, however, [are] disputed." (EXCERPT)^ieng

Conformation of d(GGGATCCC)2 in crystals and in solution studied by X-ray diffraction, Raman spectroscopy and molecular modelling.

In the crystal, d(GGGATCCC)2 forms an A-DNA double helix as known from a single crystal X-ray diffraction study. Accordingly, in the Raman spectra of crystals the A-family marker bands at 664, 705, 807 and 1101 cm-1 and the spectral characteristics in the region 1200 to 1500 cm-1 clearly demonstrate the A-form as the dominant conformation. Bands at 691, 850, and 1080 cm-1, however, indicate that a minor fraction of the octamer molecules in the crystal is in an unusual, still not unequivocally identified conformation possibly belonging to the B-family. In solution, the octamer is in B-like conformation as shown by the presence of B-DNA Raman marker bands at 685, 837, 1094 and 1421 cm-1. Molecular modelling techniques lead to three structures with slightly different B-form geometries as the lowest energies models when a sigmoidal dielectric function with the bulk dielectric constant epsilon = 78 and the value q = -0.5e for the effective phosphate charges was used in the calculations. An A-form structure bearing a strong resemblance to the experimentally determined crystal structure becomes the lowest energy model structure when the electrostatic parameters are changed to epsilon = 30 and q = -0.25e, respectively.

Novel thiosemicarbazones derived from formyl- and acyldiazines: synthesis, effects on cell proliferation, and synergism with antiviral agents.

The synthesis of a series of novel thiosemicarbazones (TSC's) derived from various alkyl diazinyl (3-pyridazinyl, 4-pyrimidinyl, 2-pyrazinyl) ketones and 3-pyridazinecarbaldehyde and their evaluation against herpes simplex virus (HSV) and human immunodeficiency virus (HIV) as well as the determination of their cytotoxicity are described. In addition, the effects of combination of such TSC's with the well-known antiviral drugs acyclovir (ACV) and 3'-azido-3'-deoxythymidine (AZT) were studied. Under our experimental conditions, i.e. determination of virus-induced cytopathic effect upon infection of HUT78 cells with HSV-1 and upon infection of MT4 cells with HIV-1, no antiviral activity could be detected with any of the TSC's. However, pronounced effects on proliferation of these rapidly growing T4 lymphocyte cell lines were observed. Clear structure-activity relationships with regard to these cytotoxic effects could be established: compared to pyridine, pyrazine, or pyrimidine-derived TSC's most of the 3-pyridazinyl congeners investigated are less cytotoxic; introduction of a methyl group into C-6 of the pyridazine system or prolongation of the acyl moiety in these compounds has essentially no influence; all compounds bearing an N,N-dimethylamino or a cycloamino substituent are much more toxic than those with an NH2 or NHR substituent; the nature of R in the latter type of compounds has only moderate influence. It has been reported that combination of TSC's with the antiviral agent acyclovir (ACV) results in potentiation of this well-known drug. We evaluated the potential of our series of novel TSC's in combination with ACV for inhibition of HSV-1-induced cytopathic effect in HUT78 cells and in combination with 3'-azido-3'-deoxythymidine (AZT) for inhibition of HIV-1-induced cytopathic effect in MT4 cells. Only four compounds out of this series, all characterized by an unsubstituted NH2 group, exhibited moderate synergism with the above mentioned antiviral drugs. Our results do not support the previously expressed opinion that TSC's are selective antiviral agents. In our test systems no evidence for inhibition of virus-induced cytopathic effect was obtained. The TSC derivatives exhibited a broad range of cytotoxic effects, some at concentrations considerably below those reported to have antiviral efficacy. Several of our novel diazine-derived compounds proved advantageous over the previously described pyridine analogues with regard to cytotoxicity. Moderate synergism could be detected for relatively noncytotoxic TSC's with the antiviral drugs ACV (antiherpes) and AZT (anti-HIV).

[Thiophene as a structural element in physiologically active substances. 18. A thiophene analog of propafenone]. / Thiophen als Strukturelement physiologisch aktiver Substanzen, 18. Mitt.: Ein Thiophenanalogon des Propafenons.

The preparation of compounds 1, which are thiophene analogues of propafenon (A) is described. Compound 1a shows antiarrhythmic activity in various in vivo test-systems.

[Education of terminally ill patients from the legal viewpoint]. / Die Aufklärung unheilbar Kranker aus rechtlicher Sicht.

The duty of doctors to inform their patients about their state of health and diagnosis is not as strict as the duty to inform about the risks of the treatment and the duty to give the patients correct medical instructions how to behave during the treatment. The negligent violation of this duty does generally not cause a criminal or civil liability. The doctor generally has the right to give this information in a most regardful way if a patient does not insist on a full information about diagnosis and prognosis. In case of the doctor's conviction that the patient is physically or psychically not capable to bear the truth, the doctor is entitled to be silent about the patient's real state of health.

Synthesis and antiviral activity of thiosemicarbazone derivatives of pyridazinecarbaldehydes and alkyl pyridazinyl ketones.

Various novel thiosemicarbazones (TSCs) 15b-e, 16b-e, 17b-e, 18b-e, and 19b-e derived from 4-pyridazinecarbaldehyde, 3-pyridazinecarbaldehyde, 4-acetylpyridazine, 3-acetylpyridazine, and 3-propionylpyridazine were prepared and their cytotoxic and antiherpetic potentials were evaluated. It was found that the replacement of the 2-pyridylmoiety in aldehyde derived compounds 20a-c by a 4-pyridazinyl group (compounds 15b-d) abolishes biological activity. However, in TSCs derived from 3-pyridazinecarbaldehyde (16b-d) the cytotoxic potency was considerably reduced (factor approximately 300), while the antiviral activity was largely retained. A total loss of biological activity occurred when the pyridyl group in TSC 20d, derived from 2-acetylpyridine, was replaced by the 4-pyridazinyl system (17d). By employment of the 3-pyridazinyl unit for isosteric modification, however, the cell toxicity could be reduced significantly (factor 100) without impairing the antiherpetic potential also in the series of TSCs derived from N-heteroaromatic ketones. It was observed that there is no obvious influence of the size of the cycloamino substituent on the biological activities in compounds 20a-d, 15b-d, 16b-d, 17b-d, and 18b-d. While the pyridine derived TSCs in our experiments proved clearly cytotoxic at lower concentrations than those being antivirally active, the aza-analogous compounds derived from 3-acetylpyridazine (18b-e) inhibited plaque formation at concentrations equal to those causing cytotoxic effects.(ABSTRACT TRUNCATED AT 250 WORDS)