Substituenteneffekte auf die C–C-Bindungsstärke, 8. Standardbildungsenthalpien und Spannungsenthalpien von 1,1,2,2-Tetraethylethylenglykol-dimethylether und D,L-1,2-Dimethyl-1,2-diphenylethylenglykol-dimethylether

Effects of Substituents on the Strength of C - C Bonds, 8¹. - Heats of Formation and Strain of 1,1,2,2-Tetraethylethylene Glycol Dimethyl Ether and D,L .-1,2-Dimethyl-l,2-diphenylethylene Glycol Dimethyl Ether The heats of combustion of the title compounds 1 and 2 were measured calorimetrically with the result (kcal mol ^-1, s. d. in parentheses) ΔH°_c = − 1880.1 (± 0.6) and − 2373.3 (± 1.4). The heat of vaporisation of 1 ΔH^v = 14.3 (± 0.3) and the heat of sublimation of 2 ΔH^sub = 27.2 (± 0.5) were derived from their temperature dependance of the vapor pressure. The latter were determined between 30 and 80°C using a flow method. The resulting standard heats of formation ΔH°_t(g) = −122.4 (± 0.7) and −43.8 (±1.5) for 1 and 2 correspond to a strain enthalpy (_s) of 15.9 and 8.0 kcal mol^-1, respectively. The steric strain of the dimethoxyethanes 1 and 2 is about one fourth lower than the strain of the corresponding dimethylethanes 3 and 4 bearing the same substituents. Thus, a methoxy group causes less steric stress than a methyl group.     

Dendrimeric Gd(III) complex of a monophosphinated DOTA analogue: optimizing relaxivity by reducing internal motion

A marked increase of relaxivity has been observed upon rigidifying the internal frame of Gd-containing PAMAM dendrimers: the effect has been attained by either protonation of the dendrimer or by forming supramolecular adducts with cationic polyaminoacids.     

Thermodynamic Properties and Melting Behavior of Bi–Sn–Zn Alloys

Summary. The partial and integral enthalpies of mixing of liquid Bi–Sn–Zn alloys were determined at 500°C by a drop calorimetric technique using a Calvet-type microcalorimeter. The ternary interaction parameters in the Bi–Sn–Zn system were fitted using the Redlich-Kister-Muggianu model for substitutional solutions, and isoenthalpy curves of the integral molar enthalpy of mixing at 500°C were constructed. Furthermore, a DSC technique was used to determine the liquidus temperatures in three sections (3, 5, and 7 at.% Zn) as well as the invariant reaction temperature of the ternary eutectic L ⇄ (Bi) + (Sn) + (Zn). The ternary eutectic reaction was found at 135°C.     

Chelation of carbocations by polyethers and polyamines

Chelates formed by carbocations and cyclic polyethers and polyamines are studied with semiempirical and ab initio MO methods.     

Chemoenzymatic approach to enantiopure streptogramin B variants: characterization of stereoselective pristinamycin I cyclase from Streptomyces pristinaespiralis

Streptogramin B antibiotics are cyclic peptide natural products produced by Streptomyces species.In combination with the synergistic group A component, they are "last line of defense" antimicrobial agents against multiresistant cocci. The racemization sensitivity of the phenylglycine (Phg(7)) ester is a complex challenge in total chemical synthesis of streptogramin B molecules. To provide fast and easy access to novel streptogramin antibiotics, we introduce a novel chemoenzymatic strategy in which diversity is generated by standard solid phase protocols and stereoselectivity by subsequent enzymatic cyclization. For this approach, we cloned, overproduced, and biochemically characterized the recombinant thioesterase domain SnbDE TE of the pristinamycin I nonribosomal peptide synthetase from Streptomyces pristinaespiralis. SnbDE TE catalyzes regioselective ring closure of linear peptide thioester analogues of pristinamycin I as well as stereoselective cyclization out of complex in situ racemizing substrate mixtures, enabling synthesis of Streptogramin B variants via a dynamic kinetic resolution assay. A remarkable substrate tolerance was detected for the enzymatic cyclization including all the seven positions of the peptide backbone. Interestingly, SnbDE TE was observed to be the first cyclase from a macrolactone forming NRPS which is additionally able to catalyze macrolactamization of peptide thioester substrates. An N-methylated peptide bond between positions 4 and 5 is mandatory for a high substrate turnover. The presented strategy is potent to screen for analogues with improved activity and guides our understanding of structure--activity relationships in the important class of streptogramin antibiotics.     

Synthesis and derivatization of daptomycin: a chemoenzymatic route to acidic lipopeptide antibiotics

Daptomycin is a branched cyclic nonribosomally assembled acidic lipopeptide, which is the first clinically approved antibiotic of this class. Here we show that the recombinant cyclization domain of the Streptomyces coelicolor calcium-dependent antibiotic (CDA) nonribosomal peptide synthetase (NRPS) is a versatile tool for the chemoenzymatic generation of daptomycin derivatives. Linear CDA undecapeptide thioesters with single exchanges at six daptomycin-specific residues were successfully cyclized by CDA cyclase. Simultaneous incorporation of all six of these residues into the peptide backbone and elongation of the N-terminus of CDA by two residues yielded a daptomycin derivative that lacked only the beta-methyl group of l-3-methylglutamate. Bioactivity studies with several substrate analogues revealed a significant role of nonproteinogenic constituents for antibacterial potency. In accordance with acidic lipopeptides, the bioactivity of the chemoenzymatic assembled daptomycin analogue is dependent on the concentration of calcium ions. Single deletions of the four acidic residues in the peptide backbone suggest that only two aspartic acid residues are essential for antimicrobial potency. These two residues are strictly conserved among other nonribosomal acidic lipopeptides and the EF-motif of ribosomally assembled calmodulin. Based on these findings CDA cyclase is a versatile catalyst that can be used to generate novel daptomycin derivatives that are otherwise difficult to obtain by chemical modification of the parental tridecapeptide to improve further its therapeutic activity.     

Study of the development of thermoresistance in human pancreatic carcinoma cell lines using proteome analysis

In order to find candidate proteins that are potentially associated with the thermoresistant phenotype in combination with drug resistance, we analyzed the differential protein expression in vitro in the human pancreatic cancer cell line EPP85-181-P and classical and atypical multidrug-resistant variants and their thermoresistant counterparts using proteomics. This study identifies sets of proteins that may lead to the development of thermoresistance. These results provide a fundamental basis to elucidate the molecular mechanism of thermoresistance and chemoresistance phenomena that may assist the therapy of inoperable cancers.     

Syntheses of bile pigments. Part 15. First unequivocal assignment of the absolute configuration of an urobilinoid bile pigment by X-ray diffraction analysis of its synthetic precursor

(?)-(4S,16S)-8, 12-bis[de(2-carboxyethyl)]mesourobilin-IIIα hydrochloride ( 8 ) has been synthesized from the enantiomerically pure 1,4,5,10-tetrahydro-1-oxodipyrrin-9-carboxylic-acid precursor 6a whose absolute configuration was determined by X-ray diffraction analysis of the N-[(S)-1-(1-naphthyl)ethyl] carboxamide 7b . The present results prove unequivocally that an (S,S)-configurated urobilin chromophore displays a negative Cotton effect in the VIS absorption range. However, the helicity of the inherently dissymmetric chromophore remains undetermined.     

Zur Stereochemie der Vitamin D3-Epoxide Röntgenstrukturanalyse einer 5,6-7,8-Diepoxidverbindung

Epoxidation of vitamin D₃ with benzonitrile ¦H₂O₂¦ KHCO₃ (Payne's reagent) yields exclusively the 5,6-mono-oxirane2. Further epoxidation with the same reagent gives the 5,6-7,8-bisepoxide3 a. Its stereochemistry and therefore the stereochemistry of2 was established by single crystal X-ray analysis of thep-Brbenzoate3b. Thereby for the first time a directive effect of a homoallylic hydroxyl group during thePayne-epoxidation was established.

Herrn Prof.Mihailovic (Universität Belgrad) mit den besten Wünschen zum 60. Geburtstag gewidmet.     

Carnitine in Pregnancy

Summary. By the 12^th week of gestation, mean whole blood and plasma carnitine levels are already significantly (p<0.01) lower than those of controls, with a further significant (p<0.01) decrease up to parturition. Diminished carnitine levels may cause a downregulation of carnitine palmitoyltransferase1 (CPT1), both the liver isoform (CPT1A) and muscle isoform (CPT1B), carnitine palmitoyltransferase2 (CPT2), and carnitine acetyltransferase (CRAT) in white blood cells of pregnant women, as determined by real time PCR using the LightCyclerSYBR Green technology.L-Carnitine-L-tartrate supplementation of 2 g/d resulted in an up to 10-fold increase of the relative mRNA abundances of CPT1B, CPT2, and OCTN2 and a 5-fold increase of CPT1A, and CRAT.There is a relationship between the relative mRNA levels of CPT1A and CPT1B and the FFA plasma levels. The substitution of 2 g L-carnitine-L-tartrate/d resulted in significant (p<0.001) lower FFA levels compared to untreated controls and the groups substituted with 0.5 and 1 g L-carnitine/d although plasma carnitine levels were not significantly increased. The most substantial effect was the reduced portion of acylcarnitines on total carnitine in those women receiving 2 g L-carnitine-L-tartrate.Carnitine substitution resulted in an enhanced excretion of both, free carnitine and acylcarnitines, whereas acetylcarnitine accounts for 50–65% of total acylcarnitines.The results of the present study provide evidence that L-carnitine supplementation in pregnancy in sufficient doses avoids a striking increase of plasma FFAs, which are thought to be the main cause of insulin resistance and consequently gestational diabetes mellitus (GDM).