2-Methylsulfanylbenzo[f]isoquinoline

S-Methylation of a 4-(naphth-2-yl)-β-thiolactam gives an intermediate 4-(naphth-2-yl) substituted 1-azetine which undergoes a [2+2] ring-opening followed by electrocyclic ring closure of the resulting 2-azadiene to give a benzo[f]isoquinolin

Intramolecular Azide to Alkene Cycloadditions for the Construction of Pyrrolobenzodiazepines and Azetidino-Benzodiazepines

The coupling of proline- and azetidinone-substituted alkenes to 2-azidobenzoic and 2-azidobenzenesulfonic acid gives precursors that undergo intramolecular azide to alkene 1,3-dipolar cycloadditions to give imine-, triazoline- or aziridine-containing pyrrolo[1,4]benzodiazepines (PBDs), pyrrolo[1,2,5]benzothiadiazepines (PBTDs), and azetidino[1,4]benzodiazepines. The imines and aziridines are formed after loss of nitrogen from a triazoline cycloadduct. The PBDs are a potent class of antitumour antibiotics

N-Alkylation and Aminohydroxylation of 2-Azidobenzenesulfonamide gives a Pyrrolobenzothiadiazepine precursor whereas attempted N-Alkylation of 2-Azidobenzamide gives Benzotriazinones and Quinazolinones

N-Alkylation of 2-azidobenzenesulfonamide with 5-bromopent-1-ene gave an N-pentenyl sulfonamide which underwent intramolecular aminohydroxylation to give an N-(2-azidoaryl)sulfonyl prolinol, a precursor for the synthesis of a pyrrolobenzothiadiazepine. The attempted N-alkylation of 2-azidobenzamide gave a separable mixture (~1:1) of a benzotriazinone and a quinazolinone in 72% combined yield. Other primary alkyl halides (3 examples) gave similar mixtures of benzotriazinones and quinazolinones. Benzylic, allylic, secondary and tertiary alkyl halides (5 examples) gave only the benzotriazinones in moderate yields. The results of mechanistic studies show the likely involvement of nitrene intermediates in the quinazolinone pathway and a second pathway involving a DMSO or dimethylsulfide mediated conversion of 2-azidobenzamide into the benzotriazinones

Effect of plasma surface treatment of poly (dimethylsiloxane) on the permeation of pharmaceutical compounds

This paper addresses the modification of poly(dimethylsiloxane), i.e. PDMS, using plasma surface treatment and a novel application of the membrane created. A set of model compounds were analysed to determine their permeation through PDMS both with, and without, plasma treatment. It was found that plasma treatment reduced permeation for the majority of compounds yet had little effect for some compounds, such as caffeine, with results indicating that polarity plays an important role in permeation, as is seen in human skin. Most importantly, a direct correlation was observed between plasma-modified permeation data and literature data through calculation of membrane permeability (Kp) values implying plasma-modified silicone membrane (PMSM) could be considered a suitable in vivo replacement to predict clinical skin permeatio

Azide based routes to tetrazolo and oxadiazolo derivatives of pyrrolobenzodiazepines and pyrrolobenzothiadiazepines

Tetrazolo- and 1,2,4-oxadiazolo-fused derivatives of the antitumour, antibiotic, DNA-interactive pyrrolo[2,1-c][1,4]benzodiazepines and their pyrrolobenzothiadiazepine derivatives have been produced as analogues of a 1,2,3-triazolo-fused pyrrolobenzothiadiazepine which was shown to be a Glut-1 transporter inhibitor with potential as an antitumour agent. The tetrazolo-fused systems were produced by intramolecular 1,3-dipolar cycloaddition between an azide and a nitrile. The 1,2,4-oxadiazolo systems were produced by nitrile oxide cycloadditions to pyrrolobenzothiadiazepines which were in turn produced from a 2-(azidobenzenesulfonyl)-1,2-thiazine 1-oxide. The latter species underwent a phosphite mediated one-pot sulfur extrusion, ring contraction and azide to amine conversion to form 1-(aminobenzenesulfonyl)pyrroles. Bischler-Napieralski ring closure gave the pyrrolobenzothiadiazepines

Strong glacial-interglacial variability in upper ocean hydrodynamics, biogeochemistry, and productivity in the southern Indian Ocean

In the southern Indian Ocean, the position of the subtropical front - the boundary between colder, fresher waters to the south and warmer, saltier waters to the north - has a strong influence on the upper ocean hydrodynamics and biogeochemistry. Here we analyse a sedimentary record from the Agulhas Plateau, located close to the modern position of the subtropical front and use alkenones and coccolith assemblages to reconstruct oceanographic conditions over the past 300,000 years. We identify a strong glacial-interglacial variability in sea surface temperature and productivity associated with subtropical front migration over the Agulhas Plateau, as well as shorter-term high frequency variability aligned with variations in high latitude insolation. Alkenone and coccolith abundances, in combination with diatom and organic carbon records indicate high glacial export productivity. We conclude that the biological pump was more efficient and strengthened during glacial periods, which could partly account for the reported reduction in atmospheric carbon dioxide concentrations. Migration of the Subtropical Front during glacial and interglacial periods resulted in variability in the strength of the biological pump in the Southern Ocean sector of the Indian Ocean, according to sedimentary records from the Agulhas Plateau.This work used samples and data provided by the IODP. We are thankful for the support from the crew of the R/V JOIDES Resolution and IODP staff. This work is funded through the Universidad de Salamanca Postdoctoral Contract supported by the Ministerio de Ciencia, Innovación y Universidades Grant RTI2018-099489-B-I00 and the German Science Foundation (DFG) Research Center/Cluster of Excellence ‘The Ocean in the Earth System' (MARUM; Grant No. 49926684). We acknowledge financial support from the National Science Foundation of the US under Award No. 1737218 (M.A.B), the European Union’s Horizon 2020 Research and Innovation Programme under the Marie Sklodowska Curie Grant Agreement No. 799531 (M.S.P.), and the Spanish Ministry of Science and Innovation Grant CTM2017-89711-C2-1-P, co-funded by the European Union through FEDER funds (F.J.J.E.

The last 1 million years of the extinct genus Discoaster: Plio–Pleistocene environment and productivity at Site U1476 (Mozambique Channel)

A detailed paleoenvironment reconstruction from the Mozambique Channel, western Indian Ocean, based on the calcareous nannoplankton assemblages was conducted for the interval between 2.85 and 1.85 Myr. This study covers the period during which the successive extinction of the last five species of discoasters occurred. New productivity data obtained from the abundances of the Discoaster species (Discoaster brouweri, D. triradiatus, D. pentaradiatus, D. surculus, and D. tamalis) and other indicative calcareous nannoplankton taxa showed abundance variations, which were at paced with the 100, 41, and 23 kyr astronomical periodicities. A shift in the productivity and water-column stratification proxies occurred at ~2.4 Ma, after the onset of the Northern Hemisphere glaciation. Here we propose that the variability recorded at International Ocean Discovery Program Site U1476 reflects the interplay between forcing associated with warm tropical Pacific and cold southern ocean influences. The former is shown by consistent occurrence of warm water taxa (Calcidiscus leptoporus, Oolithotus spp., Rhabdosphaera clavigera, Syracosphaera spp., Umbellosphaera spp.), typical of Indonesian Throughflow surface waters. On the other hand, the occurrence of Coccolithus pelagicus indicates the influence of cold, nutrient-rich sub-Antarctic surface waters. A more mixed water column initiated at ~2.4 Ma, and a consequent productivity increase led to the gradual reduction of the Discoaster species, until their extinction at 1.91 Ma. This period was characterized by the low values of the Florisphaera profunda index and high abundances of upper photic zone flora, indicative of nutrient-rich surface water conditions. High productivity at the location during this period could have also been amplified by localized upwelling events driven by the Mozambique Channel eddies

Budd-Chiari Syndrome: Long term success via hepatic decompression using transjugular intrahepatic porto-systemic shunt

<p>Abstract</p> <p>Background</p> <p>Budd-Chiari syndrome (BCS) generally implies thrombosis of the hepatic veins and/or the intrahepatic or suprahepatic inferior vena cava. Treatment depends on the underlying cause, the anatomic location, the extent of the thrombotic process and the functional capacity of the liver. It can be divided into medical treatment including anticoagulation and thrombolysis, radiological procedures such as angioplasty and transjugular intrahepatic porto-systemic shunt (TIPS) and surgical interventions including orthotopic liver transplantation (OLT). Controlled trials or reports on larger cohorts are limited due to rare disease frequency. The aim of this study was to report our single centre long term results of patients with BCS receiving one of three treatment options i.e. medication only, TIPS or OLT on an individually based decision of our local expert group.</p> <p>Methods</p> <p>20 patients with acute, subacute or chronic BCS were treated between 1988 and 2008. Clinical records were analysed with respect to underlying disease, therapeutic interventions, complications and overall outcome.</p> <p>Results</p> <p>16 women and 4 men with a mean age of 34 ± 12 years (range: 14-60 years) at time of diagnosis were included. Myeloproliferative disorders or a plasmatic coagulopathy were identified as underlying disease in 13 patients, in the other patients the cause of BCS remained unclear. 12 patients presented with an acute BCS, 8 with a subacute or chronic disease. 13 patients underwent TIPS, 4 patients OLT as initial therapy, 2 patients required only symptomatic therapy, and one patient died from liver failure before any specific treatment could be initiated. Eleven of 13 TIPS patients required 2.5 ± 2.4 revisions (range: 0-8). One patient died from his underlying hematologic disease. The residual 12 patients still have stable liver function not requiring OLT. All 4 patients who underwent OLT as initial treatment, required re-OLT due to thrombembolic complications of the graft. Survival in the TIPS group was 92.3% and in the OLT group 75% during a median follow-up of 4 and 11.5 years, respectively.</p> <p>Conclusion</p> <p>Our results confirm the role of TIPS in the management of patients with acute, subacute and chronic BCS. The limited number of patients with OLT does not allow to draw a meaningful conclusion. However, the underlying disease may generate major complications, a reason why OLT should be limited to patients who cannot be managed by TIPS.</p

Detailed stratified GWAS analysis for severe COVID-19 in four European populations

Given the highly variable clinical phenotype of Coronavirus disease 2019 (COVID-19), a deeper analysis of the host genetic contribution to severe COVID-19 is important to improve our understanding of underlying disease mechanisms. Here, we describe an extended genome-wide association meta-analysis of a well-characterized cohort of 3255 COVID-19 patients with respiratory failure and 12 488 population controls from Italy, Spain, Norway and Germany/Austria, including stratified analyses based on age, sex and disease severity, as well as targeted analyses of chromosome Y haplotypes, the human leukocyte antigen region and the SARS-CoV-2 peptidome. By inversion imputation, we traced a reported association at 17q21.31 to a ∼0.9-Mb inversion polymorphism that creates two highly differentiated haplotypes and characterized the potential effects of the inversion in detail. Our data, together with the 5th release of summary statistics from the COVID-19 Host Genetics Initiative including non-Caucasian individuals, also identified a new locus at 19q13.33, including NAPSA, a gene which is expressed primarily in alveolar cells responsible for gas exchange in the lung.publishedVersio