Increasing the Brønsted acidity of Ph2PO2H by the Lewis acid B(C6F5)3. Formation of an eight-membered boraphosphinate ring [Ph2POB(C6F5)2O]2

The Deutsche Forschungsgemeinschaft (DFG) is gratefully acknowledged for financial support. The theoretical part of this work was supported by the Russian Science Foundation (Project 14-13-00832).Autoprotolysis of the metastable acid (C6F5)3BOPPh2OH, prepared in situ by the reaction of the rather weak Brønsted acid Ph2PO2H with the strong Lewis acid B(C6F5)3, gave rise to the formation of the eight-membered ring [Ph2POB(C6F5)2O]2 and C6F5H. The conjugate base was isolated as stable sodium crown ether salt [Na(15-crown-5)][Ph2PO2B(C6F5)3].Publisher PDFPeer reviewe

Unkonventionelle Lewis-Paare zwischen der Lewis-Säure B(C6F5)3 mit sauerstoffatomhaltigen Lewis-Basen

Current research focuses on the synthesis of stable disaggregated p-block element-oxygen compounds. It was shown that some of them are capable of binding the greenhouse gas carbon dioxide. Furthermore, research has been conducted for more acidic BrA nsted acids, to be used in chemical synthesis and catalysis. Against this background this PhD thesis describes the Lewis acid induced disaggregation of dimeric antimony oxides (Ph3SbO)2 and 2,6-(Me2NCH2)2C6H3SbO 2 by B(C6F5)3 and the formation of Ph3SbOB(C6F5)3 and 2,6-(Me2NCH2)2C6H3SbOB(C6F5)3. In addition, it is shown that the BrAA nsted acidity of Ph2P(O)OH can be increased significantly by B(C6F5)3 resulting in the formation of the metastable acid Ph2(HO)POB(C6F5)3. Elimination of C6F5H by autoprotolysis gave rise to the eight-membered boraphosphinate ring Ph2POB(C6F5)2O 2. Furthermore, the reaction of Ph2PHO and B(C6F5)3 with (tht)AuCl provided the push-pull complex (C6F5)3BOPPh2 Au(tht) containing a zwitterionic a OPPh2Aua unit, being stabilized by a hard pulling Lewis acid and a soft pushing Lewis base. Finally, the formation of six adducts between B(C6F5)3 and archetypical alcoholates and carboxylates are described, e.g. Na(15-crown-5) CH3OAA B(C6F5)3 and Na(15-crown-5) HCO2AA B(C6F5)3

Unconventional Lewis pairs between the Lewis acid B(C6F5)3 and Lewis bases containing oxygen donor atoms

Current research focuses on the synthesis of stable disaggregated p-block element-oxygen compounds. It was shown that some of them are capable of binding the greenhouse gas carbon dioxide. Furthermore, research has been conducted for more acidic BrA nsted acids, to be used in chemical synthesis and catalysis. Against this background this PhD thesis describes the Lewis acid induced disaggregation of dimeric antimony oxides (Ph3SbO)2 and 2,6-(Me2NCH2)2C6H3SbO 2 by B(C6F5)3 and the formation of Ph3SbOB(C6F5)3 and 2,6-(Me2NCH2)2C6H3SbOB(C6F5)3. In addition, it is shown that the BrAA nsted acidity of Ph2P(O)OH can be increased significantly by B(C6F5)3 resulting in the formation of the metastable acid Ph2(HO)POB(C6F5)3. Elimination of C6F5H by autoprotolysis gave rise to the eight-membered boraphosphinate ring Ph2POB(C6F5)2O 2. Furthermore, the reaction of Ph2PHO and B(C6F5)3 with (tht)AuCl provided the push-pull complex (C6F5)3BOPPh2 Au(tht) containing a zwitterionic a OPPh2Aua unit, being stabilized by a hard pulling Lewis acid and a soft pushing Lewis base. Finally, the formation of six adducts between B(C6F5)3 and archetypical alcoholates and carboxylates are described, e.g. Na(15-crown-5) CH3OAA B(C6F5)3 and Na(15-crown-5) HCO2AA B(C6F5)3

Amyloid β chaperone — lipocalin-type prostaglandin D synthase acts as a peroxidase in the presence of heme

The extracellular transporter, lipocalin-type prostaglandin D synthase (L-PGDS) binds to heme and heme metabolites with high affinity. It has been reported that L-PGDS protects neuronal cells against apoptosis induced by exposure to hydrogen peroxide. Our study demonstrates that when human WT L-PGDS is in complex with heme, it exhibits a strong peroxidase activity thus behaving as a pseudo-peroxidase. Electron paramagnetic resonance studies confirm that heme in the L-PGDS-heme complex is hexacoordinated with high-spin Fe(III). NMR titration of heme in L-PGDS points to hydrophobic interaction between heme and several residues within the beta-barrel cavity of L-PGDS. In addition to the transporter function, L-PGDS is a key amyloid beta chaperone in human cerebrospinal fluid. The presence of high levels of bilirubin and its derivatives, implicated in Alzheimer's disease, by binding to L-PGDS may reduce its chaperone activity. Nevertheless, our ThT binding assay establishes that heme and heme metabolites do not significantly alter the neuroprotective chaperone function of L-PGDS. Guided by NMR data we reconstructed the heme L-PGDS complex using extensive molecular dynamics simulations providing a platform for mechanistic interpretation of the catalytic and transporting functions and their modulation by secondary ligands like A beta peptides and heme metabolites

Role of Dispersion in Metallophilic Hg···M Interactions (M = Cu, Ag, Au) within Coinage Metal Complexes of Bis(6-diphenylphosphinoacenaphth-5-yl)mercury

The previously reported bis­(6-diphenylphosphinoacenaphth-5-yl)mercury (<b>1</b>) was used as ligand for the preparation of the copper­(I) complexes, <b>1</b>·CuCl and [<b>1</b>·Cu­(NCMe)]­BF₄, which were characterized by multinuclear NMR spectroscopy and X-ray crystallography. DFT calculations employing topological analysis of the electron and electron pair densities within the AIM and ELI-D space-partitioning schemes revealed significant metallophilic Hg···Cu interactions. Evaluation of noncovalent bonding aspects according to the noncovalent interaction (NCI) index was applied not only for the Cu complexes <b>1</b>·CuCl and [<b>1</b>·Cu­(NCMe)]­BF₄ but also for the previously reported Ag and Au complexes, namely, [<b>1</b>·MCl] (M = Ag, Au) and [<b>1</b>·M­(NCMe)_<i>n</i>]⁺ (M = Ag, <i>n</i> = 2; M = Au, <i>n</i> = 0), and facilitated the assignment of attractive dispersive Hg···M interactions with the Hg···Cu contacts being comparable to the Hg···Ag but weaker than the Hg···Au interactions. The localization of the attractive noncovalent bonding regions increases in the order Cu < Ag < Au

Increasing the Brønsted acidity of Ph₂PO₂H by the Lewis acid B(C₆F₅)₃. Formation of an eight-membered boraphosphinate ring [Ph₂POB(C₆F₅)₂O]₂

Autoprotolysis of the metastable acid (C6F5)3BOPPh2OH, prepared in situ by the reaction of the rather weak Brønsted acid Ph2PO2H with the strong Lewis acid B(C6F5)3, gave rise to the formation of the eight-membered ring [Ph2POB(C6F5)2O]2 and C6F5H. The conjugate base was isolated as stable sodium crown ether salt [Na(15-crown-5)][Ph2PO2B(C6F5)3].</p

Development and validation of deep learning classifiers to detect Epstein-Barr virus and microsatellite instability status in gastric cancer: a retrospective multicentre cohort study

BACKGROUND: Response to immunotherapy in gastric cancer is associated with microsatellite instability (or mismatch repair deficiency) and Epstein-Barr virus (EBV) positivity. We therefore aimed to develop and validate deep learning-based classifiers to detect microsatellite instability and EBV status from routine histology slides. METHODS: In this retrospective, multicentre study, we collected tissue samples from ten cohorts of patients with gastric cancer from seven countries (South Korea, Switzerland, Japan, Italy, Germany, the UK and the USA). We trained a deep learning-based classifier to detect microsatellite instability and EBV positivity from digitised, haematoxylin and eosin stained resection slides without annotating tumour containing regions. The performance of the classifier was assessed by within-cohort cross-validation in all ten cohorts and by external validation, for which we split the cohorts into a five-cohort training dataset and a five-cohort test dataset. We measured the area under the receiver operating curve (AUROC) for detection of microsatellite instability and EBV status. Microsatellite instability and EBV status were determined to be detectable if the lower bound of the 95% CI for the AUROC was above 0·5. FINDINGS: Across the ten cohorts, our analysis included 2823 patients with known microsatellite instability status and 2685 patients with known EBV status. In the within-cohort cross-validation, the deep learning-based classifier could detect microsatellite instability status in nine of ten cohorts, with AUROCs ranging from 0·597 (95% CI 0·522–0·737) to 0·836 (0·795–0·880) and EBV status in five of eight cohorts, with AUROCs ranging from 0·819 (0·752–0·841) to 0·897 (0·513–0·966). Training a classifier on the pooled training dataset and testing it on the five remaining cohorts resulted in high classification performance with AUROCs ranging from 0·723 (95% CI 0·676–0·794) to 0·863 (0·747–0·969) for detection of microsatellite instability and from 0·672 (0·403–0·989) to 0·859 (0·823–0·919) for detection of EBV status. INTERPRETATION: Classifiers became increasingly robust when trained on pooled cohorts. After prospective validation, this deep learning-based tissue classification system could be used as an inexpensive predictive biomarker for immunotherapy in gastric cancer. FUNDING: German Cancer Aid and German Federal Ministry of Health

Aryl hydrocarbon receptor nuclear translocator-like (ARNTL/BMAL1) is associated with bevacizumab resistance in colorectal cancer via regulation of vascular endothelial growth factor A.

BACKGROUND: The identification of new biomarkers and the development of novel, targetable contexts of vulnerability are of urgent clinical need in drug-resistant metastatic colorectal cancer (mCRC). Aryl-Hydrocarbon-Receptor-Nuclear-Translocator-Like (ARNTL/BMAL1) is a circadian clock-regulated transcription factor promoting expression of genes involved in angiogenesis and tumour progression. We hypothesised that BMAL1 increases expression of the vascular endothelial growth factor A VEGFA gene and, thereby, confers resistance to anti-angiogenic therapy with bevacizumab (Beva), a clinically used antibody for neutralization of VEGFA. METHODS: PCR and immunohistochemistry were employed to assess BMAL1 expression in mice (C57BL/6 J FINDINGS: In murine CRCs, high BMAL1 expression correlated with poor preclinical response to Beva treatment. In CRC patients' tumours (n = 74), high BMAL1 expression was associated with clinical non-response to combination chemotherapy with Beva (*p = .0061) and reduced progression-free survival (PFS) [*p = .0223, Hazard Ratio (HR) = 1.69]. BMAL1 SNPs also correlated with shorter PFS (rs7396943, rs7938307, rs2279287) and overall survival (OS) [rs11022780, *p = .014, HR = 1.61]. Mechanistically, Nuclear-Receptor-Subfamily-1-Group-D-Member-1 (NR1D1/REVERBA) bound a - 672 bp Retinoic-Acid-Receptor-Related-Orphan-Receptor-Alpha-responsive-element (RORE) adjacent to a BMAL1 DNA-binding motif (E-box) in the VEGFA gene promoter, resulting in increased VEGFA synthesis and proliferation of human CRC cell lines. INTERPRETATION: BMAL1 was associated with Beva resistance in CRC. Inhibition of REVERBA-BMAL1 signalling may prevent resistance to anti-angiogenic therapy. FUND: This work was in part supported by the European Commission Seventh Framework Programme (Contract No. 278981 [ANGIOPREDICT]).</p