Protic NHC Iridium Complexes with beta-H Reactivity-Synthesis, Acetonitrile Insertion, and Oxidative Self-Activation

Protic NHC iridium complexes, obtained from the corresponding azido-phenylene-isocyanide precursor complexes, were investigated for ligand-based reactivity. Under redox-neutral conditions, acetonitrile inserts into the N-H bonds to provide kappa(2)-NHC-imidoyl ligand-based complexes, while under reductive conditions the complex also expels one N-H proton to provide the corresponding deprotonated analogues. Using zinc as a reductor activates the NHC-iridium complex to form an asymmetric bimetallic iridium hydrido complex, in which two anionic N-deprotonated NHCs bridge the bimetallic core. X-ray crystal structures are reported for the azido-phenylene-isocyanide precursor complex, the protic NHC complex, and the asymmetric bimetallic iridium hydride complex. Density functional computations and a QTAIM analysis of the bimetallic iridium hydrido complex are provided.Peer reviewe

Risk of Bias Assessments and Evidence Syntheses for Observational Epidemiologic Studies of Environmental and Occupational Exposures: Strengths and Limitations.

BACKGROUND: Increasingly, risk of bias tools are used to evaluate epidemiologic studies as part of evidence synthesis (evidence integration), often involving meta-analyses. Some of these tools consider hypothetical randomized controlled trials (RCTs) as gold standards. METHODS: We review the strengths and limitations of risk of bias assessments, in particular, for reviews of observational studies of environmental exposures, and we also comment more generally on methods of evidence synthesis. RESULTS: Although RCTs may provide a useful starting point to think about bias, they do not provide a gold standard for environmental studies. Observational studies should not be considered inherently biased vs. a hypothetical RCT. Rather than a checklist approach when evaluating individual studies using risk of bias tools, we call for identifying and quantifying possible biases, their direction, and their impacts on parameter estimates. As is recognized in many guidelines, evidence synthesis requires a broader approach than simply evaluating risk of bias in individual studies followed by synthesis of studies judged unbiased, or with studies given more weight if judged less biased. It should include the use of classical considerations for judging causality in human studies, as well as triangulation and integration of animal and mechanistic data. CONCLUSIONS: Bias assessments are important in evidence synthesis, but we argue they can and should be improved to address the concerns we raise here. Simplistic, mechanical approaches to risk of bias assessments, which may particularly occur when these tools are used by nonexperts, can result in erroneous conclusions and sometimes may be used to dismiss important evidence. Evidence synthesis requires a broad approach that goes beyond assessing bias in individual human studies and then including a narrow range of human studies judged to be unbiased in evidence synthesis. https://doi.org/10.1289/EHP6980

Adding Help to an HLA-A*24:02 Tumor-Reactive γδTCR Increases Tumor Control

γδT cell receptors (γδTCRs) recognize a broad range of malignantly transformed cells in mainly a major histocompatibility complex (MHC)-independent manner, making them valuable additions to the engineered immune effector cell therapy that currently focuses primarily on αβTCRs and chimeric antigen receptors (CARs). As an exception to the rule, we have previously identified a γδTCR, which exerts antitumor reactivity against HLA-A*24:02-expressing malignant cells, however without the need for defined HLA-restricted peptides, and without exhibiting any sign of off-target toxicity in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mouse models. This particular tumor-HLA-A*24:02-specific Vγ5Vδ1TCR required CD8αα co-receptor for its tumor reactive capacity when introduced into αβT cells engineered to express a defined γδTCR (TEG), referred to as TEG011; thus, it was only active in CD8+ TEG011. We subsequently explored the concept of additional redirection of CD4+ T cells through co-expression of the human CD8α gene into CD4+ and CD8+ TEG011 cells, later referred as TEG011_CD8α. Adoptive transfer of TEG011_CD8α cells in humanized HLA-A*24:02 transgenic NSG (NSG-A24:02) mice injected with tumor HLA-A*24:02+ cells showed superior tumor control in comparison to TEG011, and to mock control groups. The total percentage of mice with persisting TEG011_CD8α cells, as well as the total number of TEG011_CD8α cells per mice, was significantly improved over time, mainly due to a dominance of CD4+CD8+ double-positive TEG011_CD8α, which resulted in higher total counts of functional T cells in spleen and bone marrow. We observed that tumor clearance in the bone marrow of TEG011_CD8α-treated mice associated with better human T cell infiltration, which was not observed in the TEG011-treated group. Overall, introduction of transgenic human CD8α receptor on TEG011 improves antitumor reactivity against HLA-A*24:02+ tumor cells and further enhances in vivo tumor control

Cryo-electron microscopy structure and potential enzymatic function of human six-transmembrane epithelial antigen of the prostate 1 (STEAP1)

Six-transmembrane epithelial antigen of the prostate 1 (STEAP1) is an integral membrane protein that is highly up-regulated on the cell surface of several human cancers, making it a promising therapeutic target to manage these diseases. It shares sequence homology with three enzymes (STEAP2–STEAP4) that catalyze the NADPH-dependent reduction of iron(III). However, STEAP1 lacks an intracellular NADPH-binding domain and does not exhibit cellular ferric reductase activity. Thus, both the molecular function of STEAP1 and its role in cancer progression remain elusive. Here, we present a ∼3.0-Å cryo-EM structure of trimeric human STEAP1 bound to three antigen-binding fragments (Fabs) of the clinically used antibody mAb120.545. The structure revealed that STEAP1 adopts a reductase-like conformation and interacts with the Fabs through its extracellular helices. Enzymatic assays in human cells revealed that STEAP1 promotes iron(III) reduction when fused to the intracellular NADPH-binding domain of its family member STEAP4, suggesting that STEAP1 functions as a ferric reductase in STEAP heterotrimers. Our work provides a foundation for deciphering the molecular mechanisms of STEAP1 and may be useful in the design of new therapeutic strategies to target STEAP1 in cancer

N-Donor Ligand Supported “ReO2+”: A Pre-Catalyst for the Deoxydehydration of Diols and Polyols

A selected number of tetradentate N2Py2 ligand-supported ReO2+ complexes and a monodentate pyridine-supported ReO2+ complex have been investigated as catalysts for the deoxydehydration (DODH) of diols and polyols. In situ 1H NMR experiments showed that these N-donor ligand-supported ReO2+ complexes are only the pre-catalyst of the DODH reaction. Treatment of (N2Py2) ReO2+ with an excess amount of water generates an active species for DODH catalysis; use of the Re-product of this reaction shows a much shorter induction period compared to the pristine complex. No ligand is coordinated to the “water-treated” complex indicating that the real catalyst is formed after ligand dissociation. IR analysis suggested this catalyst to be a rhenium-oxide/hydroxide oligomer. The monodentate pyridine ligand is much easier to dissociate from the metal center than a tetradentate N2Py2 ligand, which makes the Py4ReO2+-initiated DODH reaction more efficient. For the Py4ReO2+-initiated DODH of diols and biomass-based polyols, both PPh3 and 3-pentanol could be used as a reductant. Excellent olefin yields are achieved

Triethanolaminate iron perchlorate revisited: change of space group, chemical composition and oxidation states in [Fe7(tea)3(tea-H)3](ClO4)2 (tea-H3 is tri­ethano­lamine)

The X-ray crystal structure of tris­[N-(2-hy­droxy­eth­yl)-2,2′-imino­di­ethano­l­ato]tris­(2,2′,2′′-nitrilo­tri­ethano­lato)tetra­iron(II)triiron(III) bis­(perchlorate), [Fe7(C6H12NO3)3(C6H13NO3)3](ClO4)2 or [Fe7(tea)3(tea-H)3](ClO4)2 (tea-H3 is tri­­ethano­lamine), is known from the literature [Liu et al. (2008). Z. Anorg. Allg. Chem. 634, 778–783] as a hepta­nuclear coordination cluster. The space group was given as I213 and is reinvestigated in the present study. We find a new space-group symmetry of Pa\overline{3} and could detect O—H hydrogens, which were missing in the original publication. Consequences on the Fe oxidation states are investigated with the bond-valence method, resulting in a mixed-valence core of four FeII and three FeIII centres. Symmetry relationships between the two space groups and the average supergroup Ia\overline{3} are discussed in detail

2-(2′-Pyridyl)-4,6-diphenylphosphinine versus 2-(2′-pyridyl)-4,6-diphenylpyridine: Synthesis and characterization of novel Cr⁰, Mo⁰ and W⁰ carbonyl complexes containing chelating P,N and N,N ligands

Replacing nitrogen by phosphorus in otherwise similar structures changes the properties of the resulting compounds significantly due to the electronic differences that exist between these heteroatoms. While the "hard" nitrogen atom of the pyridine moiety acts as a good σ-donor, the "soft" phosphorus atom of the phosphinine core results in a rather strong π-acceptor capacity. A series of novel group 6 complexes [M(CO)4(L^L)] (M = Cr0, Mo0, W0) have been synthesized, in which L^L is either 2-(2′-pyridyl)-4,6-diphenylphosphinine (P,N) or the corresponding bipyridine derivative, 2-(2′-pyridyl)-4,6-diphenylpyridine (N,N) as a chelating, bidentate ligand. The here presented results describe a detailed investigation of the structural and spectroscopic properties of the coordination compounds [M(CO)4(P,N)] and [M(CO)4(N,N)] (M = Cr0, Mo0, W0), leading to a better understanding of such intriguing aromatic phosphorus heterocycles

Re(I) complexes of pyridyl-phosphinines and 2,2’-bipyridine derivatives: A comparison study

The coordination chemistry of 2‐(2′‐pyridyl)‐4,6‐diarylphosphinines towards ReI has been investigated and compared to the structurally analogous 2,2′‐bipyridine derivatives. The different steric properties of the chelating pyridylphosphinines with respect to substituted bipyridines lead to considerable differences in the structures of the mononuclear [(P^N)Re(CO)3X] and [(N^N)Re(CO)3X] (X = Cl, Br) complexes, both in the solid state and in solution. The phosphinine‐based coordination compounds are highly sensitive towards nucleophilic attack and react reversibly with water at the P=C double bond

Selective Synthesis of Hetero-Sequenced Aza-Cyclophanes

The selective synthesis of purely organic cages withhetero-sequenced functionalized cavities is demonstrated. Thestrategy to obtain these compounds is based on a stepwiseapproach using thermodynamically controlled imine condensa-tions. To accomplish this, the amine building blocks carry addi-tional azide groups, which act as masked amines and enablethe synthesis of the desired cavities. This approach offers a precise control of interior functionalization, the substitution pat-tern and the cage size, which is demonstrated by the selectivesynthesis of four cages. The largest described cage has beeninvestigated towards its ability for guest encapsulation and isable to selectively encapsulate functionalized arenes that offera matching substitution pattern