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A concise enantioselective total synthesis of the neoclerodane diterpene (−)‐salvinorin A is reported. The stereogenic center at C‐12 was installed by catalytic asymmetric propargylation with excellent enantioselectivity, and the remaining six stereogenic centers were set up highly diastereoselectively under substrate control. As for our previous synthesis of racemic salvinorin A, two intramolecular Diels‐Alder reactions were applied to generate the tricyclic core. A chemoselective Mitsunobu inversion of a syn 1,2‐diol allowed for further streamlining of the original reaction sequence by two steps. Overall, (−)‐salvinorin A was synthesized in only 16 steps starting from 3‐furaldehyde with 1.4 % total yield. Furthermore, an alternative intramolecular Diels‐Alder strategy employing a 2‐bromo‐1,3‐diene moiety was investigated., A divine sage: The potent KOR agonist (−)‐salvinorin A was synthesized in only sixteen steps by modification of our previous route to the racemic title compound. Transition to asymmetric synthesis succeeded by a highly enantioselective propargylation to install the stereogenic center at C‐12. Shortening of the original reaction sequence by two steps was finally achieved using a chemoselective Mitsunobu esterification of a cyclic syn 1,2‐diol. Furthermore, an alternative intramolecular Diels‐Alder strategy employing a 2‐bromo‐1,3‐diene moiety was investigated.

(−)-Isoguaiene was prepared from (S)-citronellal in only 9–10 steps with good overall yields. Either a trienyne or a dienediyne metathesis and highly diastereoselective organocatalytic Michael additions of aldehydes derived from (S)-citronellal served as the key transformations.

Thermal decomposition of an iron-based MOF was conducted under controlled gas environments to understand the resulting porous carbon structure. Different phases and crystallite sizes of iron oxide are produced based on the specific gas species. In particular, air results in iron(III) oxide, and D2O and CO2 results in the mixed valent iron (II,III) oxide. Performing the carbonization under non-oxidative or reducing conditions (N2, He, H2) results in the formation of a mixture of both iron (II,III) oxide and iron (III) oxide. Based on in situ and air free handling experiments, it was observed that this is partially due to the formation of zero-valent iron metal that is rapidly oxidized when exposed to air. Neutron pair distribution function analysis provided insight into the effect of the gas environment on the local structure of the porous carbon, indicating a noticeable change in local order between the D2O and the N2 calcined samples.

Pyrazoles, thiazoles and fused thiazoles have been reported to possess many biological activities. 3-Methyl-5-oxo-4-(2-arylhydrazono)-4,5-dihydro-1H-pyrazole-1-carbothioamides3a,b(obtained from the reaction of ethyl 3-oxo-2-(2-arylhydrazono)butanoates1a,bwith thiosemicarbazide) could be transformed into a variety of thiazolyl-pyrazole derivatives6a–h,10a–c,15a–c,17,19and21via their reaction with a diversity hydrazonoyl chlorides as well as bromoacetyl derivatives. Moreover, the computational studies were carried out for all new compounds. The results indicated that five compounds showed promising binding affinities(10a: − 3.4 kcal/mol,6d: − 3.0 kcal/mol,15a: − 2.2 kcal/mol,3a: − 1.6 kcal/mol, and21: − 1.3 kcal/mol) against the active site of the epidermal growth factor receptor kinase (EGFR). The cytotoxicity of the potent products3a,6d,10a,15a, and21was examined against human liver carcinoma cell line (HepG-2) and revealed activities close to Doxorubicin standard drug. There was an understanding between the benefits of restricting affinities and the data obtained from the practical anticancer screening of the tested compounds.

Grinding a mixture of 6-aminopyrimidine-2,4(1H,3H)-dione 1a or 6-amino-2-thioxo-2,3-dihydropyrimidine-4(1H)-one 1 b or ethyl 7-amino-5-oxo-1-aryl-1,5-dihydro[1,2,4]-triazolo[4,3-a]pyrimidine-3-carboxylate derivatives 5a–c with 1,2-diphenylethanone 2 and aromatic aldehydes 3a–j in the presence of aluminate sulfonic acid nanoparticles (ASA NPs) in a one pot solvent-free conditions, afforded the pyrido[2,3-d]pyrimidinone derivatives 4a–o and ethyl 5-oxo-1-aryl-6,7,8-triphenyl-1,5,6,9-tetrahydropyrido[2,3-d][1,2,4]triazolo[4,3-a]pyrimidine-3-carboxylate derivatives 6a–c, respectively. High yields, short reaction time, easy workup, inexpensive, and reusability of the catalyst are advantages of this method. All structures were elucidated by spectral and elemental analyses. Structures of 6a–c were further proved by alternative synthesis of 6a.

Treatment of 2,4-diphenylbutadiene-1,4-sultone with hydrazine in boiling EtOH gives 1-amino- 2,4-diphenyl-1H-pyrrole. On treatment of 2,4-diphenylbutadiene-1,4 -sultone with phenyl hydrazine in glacial acetic acid, 4,5-dihydro-5-met hyl-1,3,5-triphenyl-1H-pyrazole was isolated. On the other hand, 2,4-diphenylbutadiene-1,4-sulton e reacts with 4 H-1,2,4-triazol-3-amine and 5-amino-3-phenyl-1H-pyrazole to afford the novel heterocyclic compounds 2-(2,2-dioxo-4- phenyl-3,4-dihydro-8H-2λ 6 -(1,2,4)triazolo(5,1- c)(1,2,4)thiadiazin-4-yl)-1-phenylethan-1-one, the structure of which was established by X-ray crystal lography, and 2-(2,2-dioxo-4,7-diphenyl-3,4- dihydro-6H-pyrazolo(5,1-c)(1,2,4)thiadiazin-4-yl)-1-phenylethan-1-one.

(−)-Oxyphyllol was prepared in only 4 steps from an epoxy enone that already served as an intermediate for the total synthesis of the anticancer guaiane (−)-englerin A. A regio- and diastereoselective Co(II)-catalyzed hydration of the olefin and a transannular epoxide opening were used as the key reactions.

A concise route to multigram quantities of the antibacterial diterpene (+)-totarol (1) is reported. (−)-Sclareol (2) was converted to the target compound 1 using either a sixor a seven-step sequence, while only three steps were required to access (+)-totarol (1) starting from (+)-manool (9) or (+)-13-epi-manool (10), respectively. A novel one-pot intramolecular aldol condensation/ α-alkylation protocol served as the key operation for streamlining the syntheses of 1.

Gestützt auf zwei historische Quellen aus der Geschichte der basel-städtischen Lehrerinnen- und Lehrerbildung unterscheidet der Beitrag sechs Ausbildungskonzeptionen, die sich in der Schweiz in den letzten 150 Jahren realisiert haben. Die Entscheidung für eine Variante der Ausbildungskonzeption war stets verknüpft mit den Fragen nach dem geeigneten «Ort» für die Lehrerinnen- und Lehrerbildung und der dazu passenden Professionalisierungsidee. Der Beitrag unterscheidet diesbezüglich zwischen räumlicher, konzeptioneller und struktureller Situierung, was seit jeher gesellschaftlich und fachlich strittig war. Vor dem Hintergrund dieser Problematik gelangt der Beitrag zur Einschätzung, dass auch die aktuelle Situierung der pädagogischen Hochschule kaum als definitiv betrachtet werden kann.

This study evaluated parents’ experience with University of Massachusetts (UMass) Child Psychiatry Access Project (MCPAP), a consultation service to primary care providers (PCP), aimed at improving access to child psychiatry. Parent Satisfaction Questionnaire (PSQ) was sent to families referred to UMass MCPAP by their PCP, asking about their concerns leading to the referral, the satisfaction from the service provided, adequacy of the follow up plan, and outcome. Seventy nine percent of parents agreed or strongly agreed that the services provided were offered in a timely manner. Fifty percent agreed or strongly agreed that their child’s situation improved following their contact with the services. Sixty nine percent agreed or strongly agreed that the service met their family’s need. The results suggest moderate to high parental satisfaction with MCPAP model, but highlight ongoing challenges in making successful referrals for children’s mental health services in the community, following MCPAP recommendations.

In the future, there will be an increased number of cervical revision surgeries, including 4- and more-levels. But, there is a paucity of literature concerning the geometrical and clinical outcome in these challenging reconstructions. To contribute to current knowledge, we want to share our experience with 4- and 5-level anterior cervical fusions in 26 cases in sight of a critical review of literature. At index procedure, almost 50% of our patients had previous cervical surgeries performed. Besides failed prior surgeries, indications included degenerative multilevel instability and spondylotic myelopathy with cervical kyphosis. An average of 4.1 levels was instrumented and fused using constrained (26.9%) and non-constrained (73.1%) screw-plate systems. At all, four patients had 3-level corpectomies, and three had additional posterior stabilization and fusion. Mean age of patients at index procedure was 54 years with a mean follow-up intervall of 30.9 months. Preoperative lordosis C2-7 was 6.5° in average, which measured a mean of 15.6° at last follow-up. Postoperative lordosis at fusion block was 14.4° in average, and 13.6° at last follow-up. In 34.6% of patients some kind of postoperative change in construct geometry was observed, but without any catastrophic construct failure. There were two delayed unions, but finally union rate was 100% without any need for the Halo device. Eleven patients (42.3%) showed an excellent outcome, twelve good (46.2%), one fair (3.8%), and two poor (7.7%). The study demonstrated that anterior-only instrumentations following segmental decompressions or use of the hybrid technique with discontinuous corpectomies can avoid the need for posterior supplemental surgery in 4- and 5-level surgeries. However, also the review of literature shows that decreased construct rigidity following more than 2-level corpectomies can demand 360° instrumentation and fusion. Concerning construct rigidity and radiolographic course, constrained plates did better than non-constrained ones. The discussion of our results are accompanied by a detailed review of literature, shedding light on the biomechanical challenges in multilevel cervical procedures and suggests conclusions.

The human secretory phospholipase A2 group IIA (PLA2-IIA) is a lipolytic enzyme. Its inhibition leads to a decrease in eicosanoids levels and, thereby, to reduced inflammation. Therefore, PLA2-IIA is of high pharmacological interest in treatment of chronic diseases such as asthma and rheumatoid arthritis. Quercetin and naringenin, amongst other flavonoids, are known for their anti-inflammatory activity by modulation of enzymes of the arachidonic acid cascade. However, the mechanism by which flavonoids inhibit Phospholipase A2 (PLA2) remained unclear so far. Flavonoids are widely produced in plant tissues and, thereby, suitable targets for pharmaceutical extractions and chemical syntheses. Our work focuses on understanding the binding modes of flavonoids to PLA2, their inhibition mechanism and the rationale to modify them to obtain potent and specific inhibitors. Our computational and experimental studies focused on a set of 24 compounds including natural flavonoids and naringenin-based derivatives. Experimental results on PLA2-inhibition showed good inhibitory activity for quercetin, kaempferol, and galangin, but relatively poor for naringenin. Several naringenin derivatives were synthesized and tested for affinity and inhibitory activity improvement. 6-(1,1-dimethylallyl)naringenin revealed comparable PLA2 inhibition to quercetin-like compounds. We characterized the binding mode of these compounds and the determinants for their affinity, selectivity, and inhibitory potency. Based on our results, we suggest C(6) as the most promising position of the flavonoid scaffold to introduce chemical modifications to improve affinity, selectivity, and inhibition of PLA2-IIA by flavonoids.

Objective Zygapophyseal joints of the spine are often affected in ankylosing spondylitis (AS). In this study, we undertook a systematic immunohistologic evaluation of the immunopathology of the zygapophyseal joints in patients with advanced AS. Methods We obtained zygapophyseal joints from 16 AS patients undergoing polysegmental correction of kyphosis and from 10 non-AS controls (at autopsy). Immunohistologic analysis of the bone marrow was performed by analyzing the number of infiltrating T cells (CD3, CD4, CD8), B cells (CD20), osteoclasts (CD68), bone marrow macrophages (CD68), and microvessel density (CD34) per high-power field. Results Zygapophyseal joints from 6 of 16 AS patients, but from none of the controls, exhibited 2 or more CD3+ T cell aggregates, signifying persistent inflammation. Interstitial CD4+ and CD8+ T cells were significantly more frequent in AS patients compared with non-AS controls (P = 0.002 and P = 0.049, respectively). While there was no clear difference between the number of CD20+ B cells in AS patients overall compared with controls, there was a significant difference when persistently inflamed joints from patients with AS were compared with joints without active inflammation from patients with AS or joints from controls (both P = 0.03). Microvessel density in bone marrow from AS patients with active inflammation was significantly higher than that in bone marrow from controls. Conclusion This immunohistologic study of bone marrow from zygapophyseal joints demonstrates persistent inflammation in the spine of patients with AS, including those with longstanding disease. The findings of increased numbers of T cells and B cells and neoangiogenesis suggest that these features play a role in the pathogenesis of AS.

With the advent of thoracoscopy, anterior release procedures in adolescent idiopathic scoliosis (AIS) have come into more frequent use, however, the indication criteria for an anterior release in thoracic AIS are still controversial in the literature. To date, few studies have assessed the influence on spinal flexibility and no study has so far been able to show a beneficial effect on the correction rate as compared to a single posterior procedure. The objective of this study was to evaluate the influence of thoracic disc excision on coronal spinal flexibility. Six patients (5 females, 1 male) with AIS and a mean age of 15.6 years (range 13-20 years) underwent an open anterior thoracic release prior to posterior instrumentation. Cotrel dynamic traction along with radiographs of the whole spine including traction films were conducted pre- and postoperatively and were evaluated retrospectively. The mean preoperative thoracic curve was 89.7 degrees +/- 15.4 degrees (range 65 degrees-110 degrees). The flexibility rate in Cotrel traction was 22.8 +/- 8.1%. After performance of the anterior release the thoracic curve showed a mean increase of coronal correction by 5.5 degrees +/- 5.0 degrees as assessed by traction radiographs. The flexibility index changed by 6.2 +/- 5.6%. After posterior instrumentation the thoracic curve was corrected to a mean of 36.5 degrees +/- 10.1 degrees (correction rate 59.6%). Disc excision in idiopathic thoracic scoliosis only slightly increased spinal flexibility as assessed by traction films. In our view a posterior release with osteotomy of the concave ribs (concave thoracoplasty, CTP) is more effective in increasing spinal flexibility. According to our clinical experience, an anterior release prior to posterior instrumentation in AIS should only be considered in hyperkyphosis, coronal imbalance or massive curves.

In the structures of both of the title compounds, (E)-2-buten-1-yl (S)-N-(2'-methoxy-[1,1']binaphthalen-2-yl)propanimidate, C 28 H 27 NO 2 , (I), and it's methyl-substituted derivative, C 29 H 29 NO 2 , (II), the C=N bond has an E configuration. In compound (II), the position of the additional methyl group is confirmed.

The estrogenic flavanone rac-8-prenylnaringenin (8-PN) and 3 derivatives (rac-7-(O-prenyl)naringenin-4′-acetate (7-O-PN), rac-5-(O-prenyl)naringenin-4′,7-diacetate (5-O-PN), and rac-6-(1,1-dimethylallyl)naringenin (6-DMAN) were prepared by chemical synthesis and analyzed with respect to their toxicity and possible cell cycle effects in human acute myeloid leukemia (HL-60) cells. With the exception of 5-O-PN, all the other naringenins showed only weak toxic effects at concentrations below 50 μmol/l. A cell cycle analysis over several cell generations up to 4 days was carried out using the fluorescent dye carboxyfluorescein diacetate N-succinimidyl ester (CFSE) followed by propidium iodide (PI) staining at the end of the experiment. The well-studied flavonol quercetin was included in the analysis as a reference substance. All flavonoids affected cell proliferation, but the extent and the resulting changes in the proliferation pattern were specific for each substance. In contrast to the radical scavenging activity of quercetin, the tested flavanones showed no anti-oxidative properties using several different test systems. Similarly, the mitochondrial membrane potential (ΔΨm) was hardly effected by these compounds, while both menadione and quercetin strongly reduced the potential after 1 h of treatment. The reported chemical modification of interesting lead substances (like the strongly estrogenic 8-PN) presents a promising approach to modulate the properties of a relevant substance in a pharmacologically desirable way. The low toxicity and weak cytostatic properties of the tested naringenin derivatives is encouraging for further studies on known naringenin target molecules. Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

A highly enantioselective and diastereoselective Claisen rearrangement of N-arylimidates derived from an axially chiral binaphthylamine auxiliary is reported. Upon deprotonation of the imidates with lithium diethylamide, the resultant azaenolates rearrange at 0 degrees C to give anti alpha,beta-disubstituted, gamma,delta-unsaturated N-binaphthyl amides. A iodolactonization/zinc reduction sequence readily converts these amides into the corresponding carboxylic acids of 91-95% ee and allows an efficient recovery of the chiral auxiliary.

Diastereomeric isomers of epoxides 15-28 are obtained in high yield and moderate to high optical purity when N-enoylsultams 1-14 incorporating a variety of chiral sultams as the chiral induction elements are treated with urea-hydrogen peroxide/trifluoroacetic anhydride.

Ankylosing spondylitis (AS) is a chronic inflammatory disease which affects primarily the sacroiliac joints and the spine. In patients with active disease, magnetic resonance imaging (MRI) of the spine shows areas of bone marrow edema, the histopathological equivalent of which is unknown. In this study we correlate inflammation in the spine of patients with AS as revealed by histological examination with bone marrow edema as detected by MRI. We have compared the histopathological findings of zygapophyseal joints from 8 patients with AS (age: 30 to 64, disease duration 7 to 33 years) undergoing spinal surgery with findings in MRI. For histopathological analysis, we quantified infiltrates of CD3+, CD4+ and CD8+ T cells as well as CD20+ B cells immunohistochemically. Bone marrow edema was evaluated in hematoxylin and eosin stained sections and quantified as the percentage of the bone marrow area involved. All patients with AS showed interstitial mononuclear cell infiltrates and various degrees of bone marrow edema (range from 10% to 60%) in histopathological analysis. However, in only three of eight patients histopathological inflammation and edema in the zygapophyseal joints correlated with bone marrow edema in zygapophyseal joints of the lumbar spine as detected by MRI. Interestingly, two of these patients showed the highest histological score for bone marrow edema (60%). This first study correlating histopathological changes in the spine of patients with AS with findings in MRI scans suggests that a substantial degree of bone marrow inflammation and edema is necessary to be detected by MRI.