Synthesis of Enantiomerically Pure 2-Isoxacephems

(R,6R,7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid and its enantiomer have been prepared. The ring systems were formed from the corresponding enantiomerically pure N-unsubstituted -lactams. The reduction of methyl [(R,2S,3R)-3-(1-acetoxyethyl)-1-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate] has been solved via a hemi-acetal. The structure and the configuration of a new stereogenic center in this intermediate was predicted by using 2D NMR technique and unambiguously proven by x-ray.     

Synthesis of 5H-pyridazino[4,5-b]indoles and their benzofurane analogues utilizing an intramolecular Heck-type reaction

The title ring systems were prepared from pyridazin-3(2H)-one precursors in novel, efficient pathways. 2-Methylbenzo[b]furo[2,3-d]pyridazin-1(2H)-one was synthesized via a regioselective nucleophilic substitution reaction of a 2-methyl-4,5-dihalopyridazin-3(2H)-one with phenol followed by an intramolecular Heck-type reaction. The same molecule and its 6-phenyl analogue were also prepared via reaction of 2-methyl-5-iodopyridazin-3(2H)-one or 2-methyl-5-chloro-6-phenylpyridazin-3(2H)-one, respectively, with 2-bromophenol or 2-iodophenol followed by Pd-catalyzed cyclodehydrohalogenation. Moreover, a new approach for the synthesis of 2-methyl-2,5-dihydro-1H-pyridazino[4,5-b]indol-1-ones was also elaborated utilizing a Heck-type ring closure reaction on 5-[(2-bromophenyl)amino]-2-methylpyridazin-3(2H)-ones which were obtained via Buchwald-Hartwig amination of 2-methyl-5-halopyridazin-3(2H)-ones with 2-bromoaniline.     

Selectivity of methylation of some new [1,2,3]triazolo[4,5-d]pyridazines and structure elucidation by H–N NMR spectroscopy

Alkylation of some selected [1,2,3]triazolo[4,5-d]pyridazines having five or more nitrogen atoms capable for alkylation was investigated. Pyridyl derivatives substituted also on the [1,2,3]triazole ring gave quaternary pyridinium salts, whereas in the case of the analogues compounds unsubstituted at the triazole moiety, the alkylation of the triazole ring was also observed. Unambiguous structure elucidation was provided by ¹H–¹⁵N HMBC experiments which also allowed the assignment of the ¹⁵N NMR shifts.     

Synthesis and selective reactions of v-triazolo-[1,5-b]pyridazinium salts with nucleophiles. A facile access to functionalized ethenyl-1,2,3-triazoles

v-Triazolo[1,5-b]pyridazinium salts 5a-c synthesized from α-pyridazinyl ketone arylhydrazones and 2,4,4,6-tetrabromocyclohexa-2,5-dien-1-one (TBB) reacted selectively with nucleophiles to yield - besides substituted derivatives 6 - ring-opened cyano compound 9 and/or v-triazoles containing olefinic side chain 10–12 . Mechanistic considerations reveal that cation 5 reacts with nucleophiles predominantly at C-7 unless other positions are especially activated. This selectivity proved to be in good agreement with results of semiempirical quantum chemical calculations.     

Synthesis of Enantiomerically Pure 2-Isoxacephems

Summary. (R,6R,7R)-7-(1-Acetoxyethyl)-3-methyl-2-isoxacephem-4-carboxylic acid and its enantiomer have been prepared. The ring systems were formed from the corresponding enantiomerically pure N-unsubstituted -lactams. The reduction of methyl [(R,2S,3R)-3-(1-acetoxyethyl)-1-(4-methoxyphenyl)-4-oxoazetidine-2-carboxylate] has been solved via a hemi-acetal. The structure and the configuration of a new stereogenic center in this intermediate was predicted by using 2D NMR technique and unambiguously proven by x-ray.     

On Weighted Kernels of Two Posets

A recent result of Aharoni Berger and Gorelik (Order 31(1), 35–43, 2014) is a weighted generalization of the well-known theorem of Sands Sauer and Woodrow (Theory Ser. B 33(3), 271–275, 1982) on monochromatic paths. The authors prove the existence of a so called weighted kernel for any pair of weighted posets on the same ground set. In this work, we point out that this result is closely related to the stable marriage theorem of Gale and Shapley (Amer. Math. Monthly 69(1), 9–15, 1962), and we generalize Blair’s theorem by showing that weighted kernels form a lattice under a certain natural order. To illustrate the applicability of our approach, we prove further weighted generalizations of the Sands Sauer Woodrow result.     

Analyzing the Carotenoid Composition of Melilot (Melilotus officinalis (L.) Pall.) Extracts and the Effects of Isolated (All-E)-lutein-5,6-epoxide on Primary Sensory Neurons and Macrophages

Melilotus officinalis is known to contain several types of secondary metabolites. In contrast, the carotenoid composition of this medicinal plant has not been investigated, although it may also contribute to the biological activities of the drug, such as anti-inflammatory effects. Therefore, this study focuses on the isolation and identification of carotenoids from Meliloti herba and on the effect of isolated (all-E)-lutein 5,6-epoxide on primary sensory neurons and macrophages involved in nociception, as well as neurogenic and non-neurogenic inflammatory processes. The composition of the plant extracts was analyzed by high performance liquid chromatography (HPLC). The main carotenoid was isolated by column liquid chromatography (CLC) and identified by MS and NMR. The effect of water-soluble lutein 5,6-epoxide-RAMEB (randomly methylated-β-cyclodextrin) was investigated on Ca²⁺-influx in rat primary sensory neurons induced by the activation of the transient receptor potential ankyrin 1 receptor agonist to mustard-oil and on endotoxin-induced IL-1β release from isolated mouse peritoneal macrophages. (all-E)-Lutein 5,6-epoxide significantly decreased the percent of responsive primary sensory neurons compared to the vehicle-treated stimulated control. Furthermore, endotoxin-evoked IL-1β release from macrophages was significantly decreased by 100 µM lutein 5,6-epoxide compared to the vehicle-treated control. The water-soluble form of lutein 5,6-epoxide-RAMEB decreases the activation of primary sensory neurons and macrophages, which opens perspectives for its analgesic and anti-inflammatory applications.     

An electrospray mass spectrometric method for accurate mass determination of highly acid-sensitive phosphoramidites

An accurate mass determination method utilizing electrospray ionization mass spectrometry is described for analysis of several different types of phosphoramidites that are extremely acid-sensitive compounds. An earlier method, which applied a LiCl/acetonitrile system, was extended for this special application by using polymeric standards including poly(ethylene glycol) (PEG), poly(ethylene glycol) dimethyl ether (PDE) and poly(propylene glycol) (PPG). Concentrations of standards, samples and LiCl were optimized and potential impurities that affect the analyses were also investigated.     

The Arg160Trp allele of melanocortin-1 receptor gene might protect against vitiligo

Melanocortin-1 receptor (MC1R) and agouti signaling protein (ASIP) play pivotal roles in the regulation of human pigmentation. We aimed to study whether single nucleotide polymorphisms (SNPs) of the MC1R and ASIP genes contribute to the pathogenesis of the polygenic pigment skin disorder, vitiligo. The PCR-amplified, full-length MC1R gene was studied with sequence analysis, and the 3' untranslated region (3' UTR) SNP of ASIP was detected using restriction fragment length polymorphism. The allele frequency of the ASIP SNP did not show any difference between the skin type, hair color and eye color-matched 97 vitiligo patients and the 59 healthy control individuals. As one of the MC1R polymorphisms showed significantly higher incidence among fair-skinned individuals (Fitzpatrick I+II, n=140) than among dark-skinned individuals (Fitzpatrick III+IV, n=90), both vitiligo patients and controls were divided into two groups and the frequency of the MC1R alleles was studied separately in fair-skinned and dark-skinned subgroups of diseased and healthy groups. C478T, one of the MC1R SNPs studied in 108 fair-skinned vitiligo patients and in 70 fair-skinned healthy control individuals, showed a significant difference (P=0.0262, odds ratio [95% confidence interval]=3.6 [0.0046-0.1003]) in allele frequency between the two groups: the allele frequency was higher in the control group, suggesting protection against vitiligo. Computer prediction of antigenicity has revealed that the Arg160Trp amino acid change caused by this SNP results in a decrease in antigenicity of the affected peptide epitope.     

Generation of 220 mJ nanosecond pulses at a 10 Hz repetition rate with excellent beam quality in a diode-pumped Yb:YAG MOPA system

A novel all-diode-pumped master oscillator power amplifier system based on Yb:YAG crystal rods has been developed. It consists of a Q-switched oscillator delivering 3 mJ, 6.4 ns pulses at a 10 Hz repetition rate and an additional four-pass amplifier, which boosts the output energy to 220 mJ, while a close to TEM(00) beam quality could be observed. Additionally a simulation of the amplification was written that allows for further scaling considerations.