Synthese und Reaktionen von Bicyclo[6.4.0]dodecan-3-carbonsäure-Derivaten

Synthesis and Reactions of the Bicyclo[6.4.0]dodecane-3-carboxylic Acid Derivatives The synthesis and some consecutive reactions of the compounds 5-8 , derivatives of bicyclo[6.4.0]dodecane-3-carboxylic acid ( 1 ), are described. The esters 7 and 8 can be obtained by Baeyer-Villiger oxidation of 2-hydroxy-8-methyltricyclo[7.3.1.0^2,7]tridecan-13-one ( 4 ) and subsequent hydrolysis of the lactone 5 . The structure and configuration of these compounds has been evaluated by spectroscopic techniques (mainly 2D-NMR methods). The formation of 7 via 1,2-H shift and subsequent isomerization to 8 has been studied. The esters 11 and 13 are formed stereospecifically from 7 and 8 .     

Secondary deuterium kinetic isotope effects in irreversible additions of allyl reagents to benzaldehyde

The competitive kinetics of additions of allyl to benzaldehyde-h and -d from allyltributyl tin, from diisopropyltartrylallyl boronate, and from allyl bromide and zinc dust in aqueous tetrahydrofuran have inverse secondary deuterium kinetic isotope effects, SDKIEs. These inverse SDKIEs are in contrast to the normal SDKIEs that were obtained with allyl lithium and allyl Grignard, suggesting rate-determining single-electron transfer in these cases. By various MO calculations the transition state for addition of allyl boronate occurs with substantial B-O bond formation and little C-C bond formation. The magnitudes of the SDKIEs with the other two allylating reagents, when compared with reasonable equilibrium isotope effects for the addition, suggest transition states with substantial C-C bond formation.     

Terephthalamide derivatives as mimetics of helical peptides: disruption of the Bcl-x(L)/Bak interaction

A series of Bcl-x(L)/Bak antagonists, based on a terephthalamide scaffold, was designed to mimic the alpha-helical region of the Bak peptide. These molecules showed favorable in vitro activities in disrupting the Bcl-x(L)/Bak BH3 domain complex (terephthalamides 9 and 26, K(i) = 0.78 +/- 0.07 and 1.85 +/- 0.32 microM, respectively). Extensive structure-affinity studies demonstrated a correlation between the ability of terephthalamide derivatives to disrupt Bcl-x(L)/Bak complex formation and the size of variable side chains on these molecules. Treatment of human HEK293 cells with the terephthalamide derivative 26 resulted in disruption of the Bcl-x(L)/Bax interaction in whole cells with an IC(50) of 35.0 microM. Computational docking simulations and NMR experiments suggested that the binding cleft for the BH3 domain of the Bak peptide on the surface of Bcl-x(L) is the target area for these synthetic inhibitors.     

Photoactive metallocyclodextrins: sophisticated supramolecular arrays for the construction of light activated miniature devices

The introduction of photoactive metal centres onto cyclodextrin receptors opens up new possibilities for the design of sensors, wires and energy conversion systems. This tutorial review focuses on strategies involving such metallocyclodextrins for the construction of supramolecular arrays with light-activated functions. The assembly procedures for building such arrays are presented, together with the features required for their functions both as sensors for ion or small molecule detection and as wires for photoinduced long-range energy or electron transport. Systems for metal ion sensing are described where the cyclodextrin plays a mediating role in influencing the luminescence properties of an organic probe, responsive to metal binding. Small molecule sensing by the cyclodextrin cavity is realised using luminescent lanthanide or transition metal functionalised cyclodextrins. The light signal of the photoactive metal is switched on or off upon binding an analyte in the cyclodextrin cavity. The metallocyclodextrin systems that function as wires are distinguished by the controlled assembly of transition metal polypyridine and metalloporphyrin units. These units have inherent photoactivity that defines the vectorial direction of energy or electron transfer processes through the wire.     

Systematic quantification of the dynamics of newly synthesized proteins unveiling their degradation pathways in human cells

Proteins are continuously synthesized during cell growth and proliferation. At the same time, excessive and misfolded proteins have to be degraded, otherwise they are a burden to cells. Protein degradation is essential to maintain proteostasis in cells, and dysfunction of protein degradation systems results in numerous diseases such as cancer and neurodegenerative diseases. Despite the importance of protein degradation, the degradation pathways of many proteins remain to be explored. Here, we comprehensively investigated the degradation of newly synthesized proteins in human cells by integrating metabolic labeling, click chemistry, and multiplexed proteomics, and systematic and quantitative analysis of newly synthesized proteins first revealed the degradation pathways of many proteins. Bioinformatic analysis demonstrates that proteins degraded through two major pathways have distinct properties and functions. Proteins degraded through the ubiquitin-proteasome pathway contain more disordered structures, whereas those through the autophagy-lysosome pathway have significantly higher hydrophobicity. Systematic and quantitative investigation of the dynamics of newly synthesized proteins provides unprecedented and valuable information about protein degradation, which leads to a better understanding of protein properties and cellular activities.

Systematic quantification of the dynamics of newly synthesized proteins first reveals the degradation pathways of many proteins in human cells, and proteins degraded through each of the two major pathways have distinct properties and functions.     

Objective measurement of minimal erythema and melanogenic doses using natural and solar-simulated light

Very little information exists on the amount of natural and artificial UV light required to cause sunburn and tanning in individuals with very pale skin who are at the greatest risk of developing skin cancer. We have investigated minimal erythema dose (MED) and minimal melanogenic dose (MMD) in a group of 31 volunteers with Fitzpatrick skin types I and II using an Oriel 1000 W xenon arc solar simulator and natural sunlight in Sydney, Australia. We measured the erythemal and melanogenic responses using conventional visual scoring, a chromameter and an erythema meter. We found that the average MED measured visually using the artificial UV source was 68.7 +/- 3.3 mJ/cm2 (3.4 +/- 0.2 standard erythema doses [SED]), which was significantly different from the MED of sunlight, which was 93.6 +/- 5.6 mJ/cm2 (P < 0.001) (11.7 +/- 0.7 SED). We also found significant correlations between the solar-simulated MED values, the melanin index (erythema meter) and the L* function (chromameter). The average MMD (obtained in 16 volunteers only) using solar-simulated light was 85.6 +/- 4.9 mJ/cm2, which was significantly less than that measured with natural sunlight (118.3 +/- 8.6 mJ/cm2; P < 0.05). We mathematically modeled the data for both the chromameter and the erythema meter to see if we were able to obtain a more objective measure of MED and differentiation between skin types. Using this model, we were able to detect erythemal responses using the erythema index function of the erythema meter and the a* function of the chromameter at lower UV doses than either the standard visual or COLIPA methods.     

Analysis of eleven iridoid glycosides by micellar electrokinetic capillary chromatography (MECC) and screening of plant samples by partial filling (MECC)-electrospray ionisation mass spectrometry

Of ammonium, lithium and sodium salts of dodecyl sulfate studied as surfactants in the separation of iridoid glycosides by micellar electrokinetic capillary chromatography (MECC), the last one gave the best results. Eleven neutral iridoid glycosides were separated by MECC with sodium dodecyl sulfate as surfactant, and the water–micelle partition coefficients of the compounds were calculated. The separation system was coupled via a coaxial sheath flow electrospray interface to a mass spectrometer, and the partial filling technique was used in the on-line analysis. Seven plant species belonging to five genera (Plantago, Veronica, Melampyrum, Succisa and Valeriana) were screened for the iridoid glycosides by the new method that was developed. The findings confirmed those of an earlier study on five of the iridoid glycosides. Some new iridoid glycosides were found in Plantago lanceolata, Veronica spicata and V. chamaedrys.     

H-aggregation of azobenzene-substituted amphiphiles in vesicular membranes

Photochemical switching has been studied of double-tailed phosphate amphiphiles containing azobenzene units in both tails in aqueous vesicular dispersions and in mixed vesicular systems with 1,2-dioleoyl-sn-glycero-3-phosphocholine (DOPC). Since the ease of switching depends on the strength of the bilayer packing, particular emphasis has been placed on the occurrence of H-aggregation in the hydrophobic core of the vesicles. UV-vis spectrometry was employed to monitor H-aggregation and showed how this process depends on the ionic strength and on the mode of preparation of the vesicles. Two types of H-aggregates were observed in mixed DOPC vesicles with 5 mol % of azobenzene phosphate: one with lambda(max) at around 300 nm and one with lambda(max) at 305-320 nm. Those with lambda(max) at 300 nm could not be trans-cis photoisomerized, whereas those with lambda(max) at 305-320 nm are more loosely packed and can be photochemically switched. The permeability of the vesicular bilayers, as probed with leakage experiments using calcein as a fluorescent probe, was examined as another measure for the strength of bilayer packing. Leakage occurred only for DOPC vesicles containing more than 20 mol % of azobenzenephosphate, irradiated with UV light to induce trans-cis photoisomerization. We contend that detailed information on bilayer packing will be of crucial importance for fine-tuning the lateral pressure in vesicular membranes with the ultimate aim to steer the opening and closing of mechanosensitive protein channels of large conductance.