Covalent organic frameworks (COFs) offer vast structural and chemical diversity enabling a wide and growing range of applications. While COFs are well‐established as heterogeneous catalysts, so far, ...their high and ordered porosity has scarcely been utilized to its full potential when it comes to spatially confined reactions in COF pores to alter the outcome of reactions. Here, we present a highly porous and crystalline, large‐pore COF as catalytic support in α,ω‐diene ring‐closing metathesis reactions, leading to increased macrocyclization selectivity. COF pore‐wall modification by immobilization of a Grubbs‐Hoveyda‐type catalyst via a mild silylation reaction provides a molecularly precise heterogeneous olefin metathesis catalyst. An increased macro(mono)cyclization (MMC) selectivity over oligomerization (O) for the heterogeneous COF‐catalyst (MMC:O=1.35) of up to 51 % compared to the homogeneous catalyst (MMC:O=0.90) was observed along with a substrate‐size dependency in selectivity, pointing to diffusion limitations induced by the pore confinement.
A biomimetic confinement and precise spatial arrangement of catalysts in porous media can provide increased selectivity for reactions compared to homogeneous catalysis. Herein, a covalent organic framework for molecular heterogeneous olefin metathesis is presented that utilizes spatial confinement of substrates in its pores for a substrate‐size dependent and increased macro(mono)cyclization selectivity.
Abstract BACKGROUND Central nervous system (CNS) tumors with BCOR internal tandem duplication (ITD) or BCOR/L1 fusions are recently described tumor types with distinct molecular characteristics and ...poor clinical outcome. BCOR and its homologue BCORL1 are essential components of the non-canonical polycomb repressor complex (PRC) 1.1 thereby acting as epigenetic regulators exerting a profound impact on central cellular mechanisms. However, the influence of BCOR/L1-alterations on the functionality of PRC1.1 in pediatric CNS tumors remains understudied. METHODS We performed bulk as well as single-cell/nucleus RNA sequencing (scRNA-Seq) and chromatin immunoprecipitation sequencing (ChIP-Seq) of CNS tumor tissue harboring BCOR-ITD or BCOR/L1 fusions. Additionally, BCOR/L1-altered, patient-derived cell models were used for downstream in vitro analyses. RESULTS ChIP-Seq analysis demonstrated binding of both KDM2B and mutant BCOR/L1 at PRC1.1 target genes whereas PRC1/2-mediated histone modifications H3K27me3 and H2AK119ub were absent. In addition, PRC1.1 target gene loci were characterized by high H3K27ac levels indicating increased transcriptional activity in BCOR/L1 mutant samples. Indeed, PRC1.1 targets such as FGFR1, GATA6, and ERBB3 were found to be upregulated in bulk transcriptome (n=37) analyses. Using scRNA-seq (n=10), we resolved a transcriptionally distinct cell population, specific for BCOR/L1-driven CNS tumors, which expressed high levels of PRC1.1 target genes. Besides PRC1.1 target genes, the targetable receptor tyrosine kinases PDGFR/FGFR(1/3), and IGF1R were found to be upregulated in pediatric BCOR/L1-altered CNS cancers. Accordingly, drug screens of patient-derived cell models revealed sensitivity towards small molecule inhibitors targeting the respective pathways. This translated well in anti-tumor effects of the FGFR/PDGFRA inhibitor nintedanib in BCORL1::NUTM2HP-fused patient-derived xenograft bearing mice. CONCLUSIONS Our data demonstrate for the first time that BCOR/L1-altered CNS tumors are driven by dysfunction of PRC1.1 histone modifications inducing profound transcriptomic changes ultimately activating oncogenic pathways. We further identified first feasible therapeutic targets including FGFR and PDGFR which may be leveraged for improved therapy of patients suffering from this aggressive tumor type.
Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports ...on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated
-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with
-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of
-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of
and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.
Abstract
Central nervous system (CNS) tumors with BCOR internal tandem duplications (CNS-BCOR ITD) are aggressive malignancies recently included in the 2021 WHO Classification of CNS tumors. This ...entity is characterized by ITDs within the PUFD domain of BCOR, potentially interfering with protein-protein interactions and preventing non-canonical polycomb repressive complex 1.1 (ncPRC1.1) complex formation. Additionally, other BCOR alterations like frame shift mutations and gene fusions have been described. However, the underlying molecular mechanisms promoting tumor aggressiveness remain unknown. We established cell models from one patient harboring a BCOR frameshift mutation and another one with a concomitant BCORL1-fusion. Two additional models were derived from a patient with a CNS-BCOR ITD tumor. Multidrug screening uncovered high sensitivity against defined receptor tyrosine kinase (RTK) inhibitors (TKIs). In detail, ponatinib, nintedanib, and dovitinib reduced cell viability at half maximal inhibitory concentrations (IC50) in the low micro-molar range (<2.5 µM). Expression analyses of the respective TKI targets suggested fibroblast growth factor receptor 3 (FGFR3) and platelet derived growth factor receptor A (PDGFRA) as central players in this response. RTK inhibition resulted in strongly impaired downstream MAPK and Pi3K/AKT signaling. Vice versa, exposure to the RTK ligands bFGF and PDGFAA increased S6, Erk and Akt phosphorylation. Next, we treated two patients – one with a BCOR frame shift mutation/BCORL1-gene fusion and one with an ITD with nintedanib – within a multimodal treatment approach and achieving complete remission and disease stabilization, respectively. Ultimately, we analyzed respective RTK ligands in patient cerebral spinal fluid (CSF) and found FGF18 and PDGFA to correlate with tumor treatment response and progression. Summarizing, we uncover a central role of defined RTK signaling modules in the malignant phenotype of CNS-BCOR-ITD and tumors harboring BCOR alterations and elucidate their potential as therapeutic targets. Currently, we aim to dissect the interconnection between BCOR/BCORL1 alterations and RTK hyperactivation.
The outstanding diversity of Zr-based frameworks is inherently linked to the variable coordination geometry of Zr-oxo clusters and the conformational flexibility of the linker, both of which allow ...for different framework topologies based on the same linker–cluster combination. In addition, intrinsic structural disorder provides a largely unexplored handle to further expand the accessibility of novel metal–organic framework (MOF) structures that can be formed. In this work, we report the concomitant synthesis of three topologically different MOFs based on the same M6O4(OH)4 clusters (M = Zr or Hf) and methane-tetrakis(p-biphenyl-carboxylate) (MTBC) linkers. Two novel structural models are presented based on single-crystal diffraction analysis, namely, cubic c-(4,12)MTBC-M6 and trigonal tr-(4,12)MTBC-M6, which comprise 12-coordinated clusters and 4-coordinated tetrahedral linkers. Notably, the cubic phase features a new architecture based on orientational cluster disorder, which is essential for its formation and has been analyzed by a combination of average structure refinements and diffuse scattering analysis from both powder and single-crystal X-ray diffraction data. The trigonal phase also features structure disorder, although involving both linkers and secondary building units. In both phases, remarkable geometrical distortion of the MTBC linkers illustrates how linker flexibility is also essential for their formation and expands the range of achievable topologies in Zr-based MOFs and its analogues.
Perovskite-based tandem solar cells are of increasing interest as they approach commercialization. Here we use experimental parameters from optical spectroscopy measurements to calculate the limiting ...efficiency of perovskite–silicon and all-perovskite two-terminal tandems, employing currently available bandgap materials, as 42.0% and 40.8%, respectively. We show luminescence coupling between subcells (the optical transfer of photons from the high-bandgap to low-bandgap subcell) relaxes current matching when the high-bandgap subcell is a luminescent perovskite. We calculate that luminescence coupling becomes important at charge trapping rates (≤106 s–1) already being achieved in relevant halide perovskites. Luminescence coupling increases flexibility in subcell thicknesses and tolerance to different spectral conditions. For maximal benefit, the high-bandgap subcell should have the higher short-circuit current under average spectral conditions. This can be achieved by reducing the bandgap of the high-bandgap subcell, allowing wider, unstable bandgap compositions to be avoided. Lastly, we visualize luminescence coupling in an all-perovskite tandem through cross-section luminescence imaging.
Covalent immobilization of chiral dienes in mesoporous solids for asymmetric heterogeneous catalysis is highly attractive. In order to study confinement effects in bimolecular vs monomolecular ...reactions, a series of pseudo‐C2‐symmetrical tetrahydropentalenes was synthesized and immobilized via click reaction on different mesoporous solids (silica, carbon, covalent organic frameworks) and compared with homogeneous conditions. Two types of Rh‐catalyzed reactions were studied: (a) bimolecular nucleophilic 1,2‐additions of phenylboroxine to N‐tosylimine and (b) monomolecular isomerization of isoxazole to 2H‐azirne. Polar support materials performed better than non‐polar ones. Under confinement, bimolecular reactions showed decreased yields, whereas yields in monomolecular reactions were only little affected. Regarding enantioselectivity the opposite trend was observed, i.e. effective enantiocontrol for bimolecular reactions but only little control for monomolecular reactions was found.
Thiophosphate solid electrolytes containing metalloid ions such as silicon or germanium show a very high lithium-ion conductivity and the potential to enable solid-state batteries (SSBs). While the ...lithium metal anode (LMA) is necessary to achieve specific energies competitive with liquid lithium-ion batteries (LIBs), it is also well known that most of the metalloid ions used in promising thiophosphate solid electrolytes are reduced in contact with an LMA. This reduction reaction and its products formed at the solid electrolyte|LMA interface can compromise the performance of an SSB due to impedance growth. To study the reduction of these metalloid ions and their impact more closely, we used the recently synthesized Li7SiPS8 as a member of the tetragonal Li10GeP2S12 (LGPS) family. Stripping/plating experiments and the temporal evolution of the impedance of symmetric Li|Li7SiPS8|Li transference cells show a severe increase in cell resistance. We characterize the reduction of Li7SiPS8 after lithium deposition with in situ X-ray photoelectron spectroscopy, time-of-flight secondary-ion mass spectrometry, and solid-state nuclear magnetic resonance spectroscopy. The results indicate a continuous reaction without the formation of elemental silicon. For elucidating the reaction pathways, density functional theory calculations are conducted followed by ab initio molecular dynamics simulations to study the interface evolution at finite temperature. The resulting electronic density of states confirms that no elemental silicon is formed during the decomposition. Our study reveals that Li7SiPS8 cannot be used in direct contact with the LMA, even though it is a promising candidate as both a separator and a catholyte material in SSBs.
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