1,1′-Bis(diphenylphosphino)cobaltocenium (dppc)
+
, similar to 1,1′-bis(diphenylphosphino)ferrocene, can be coordinated by dicarbonylnickel(0) or cyclopentadienylnickel(
ii
), respectively. The ...cyclic voltammogram of Ni(CO)
2
(dppc)
+
(
1
+
) showed two reversible reductions, at potentails nearly identical to (dppc)
+
. The ligand-based reductions were confirmed by IR spectroelectrochemistry (SEC), although the Δ
ν
CO
was larger than might be expected if the ligand was electronically decoupled to the Ni(CO)
2
moiety. The larger Δ
ν
CO
was attibuted to changes in the donor/accpetor properties of the -PPh
2
moeities based on the occupation of the Co-Cp anti-bonding orbital, where the Cp ligand adopts an ylide-like structure. A similar analysis was performed on CpNi(dppc)
2+
(
2
2+
), where the two reductions were anodically shifted by Δ
E
= 292 and 520 mV from (dppc)
+
, indicating an increase in the M-M communication. The EPR SEC spectrum for
2
+
showed that the cobalt was reduced, while the UV-Vis-NIR SEC spectrum for
2
+
showed a NIR absportion at 1200 nm assinged as a MMCT Co
II
→ Ni
II
band. The second reduction formed
2
0
which was EPR silent but the UV-Vis-NIR SEC spectrum showed an increase in the intensity of the MMCT Co
I
→ Ni
II
.
1,1′-Bis(diphenylphosphino)cobaltocenium (dppc)
+
coordinated by dicarbonylnickel(0) or cyclopentadienylnickel(
ii
), respectively, were used to understand how ligand redox is communicated to the distal metal.
IntroductionAngiopoietin-2 (Ang2) is a secreted ligand whose concentration is increased in several cardiovascular diseases, and which causes vascular inflammation, microvessel disintegration, cardiac ...fibrosis and myocardial damage. Ang2 binds the endothelial receptor Tie2, where it competes for binding with the protective ligand Ang1. In this study we aim to develop a ligand-trap to block Ang2 action. To do this we used directed protein evolution to change the binding specificity of the Tie2 ectodomain so that it specifically binds Ang2. The evolved ectodomain will then be used as a soluble trap for introduction into the circulation to bind and sequester Ang2 preventing it from exerting its effects on the endothelium.Methods and resultsTie2 ectodomain was evolved using a novel DT40 cell surface display and evolution system. Evolutions were performed for selective binding to Ang2 by iterative cycles of mutation and selection. Variants evolved for Ang2 binding were then sequenced revealing key residues in the Ang1/2 binding domain determining ligand specificity. Fusion proteins containing the evolved variants were expressed, purified and tested for their ability to selectively bind Ang2, rather than Ang1 and Ang4. These Ang2-selective ligand-traps were found to inhibit Ang2 action on endothelial cells, inhibit adhesion of platelet/leucocyte aggregates to endothelial monolayers and suppress LPS-induced oedema.Conclusions and implicationsUsing a novel method of cell surface display and directed evolution we have evolved Tie2 ectodomain to selectively bind Ang2. This has revealed the key amino acid residues determining ligand-binding specificity of Tie2. In addition we created a series of selective Ang2 ligand-traps. These traps are almost identical to the endogenous receptor ectodomain, differing in four or fewer amino acid residues from endogenous ectodomain, and are able to inhibit the actions of Ang2. These ligand-traps have the potential for development as therapeutics to block the pathogenic and inflammatory actions of Ang2 on the cardiovascular system.
The coordination of N-heterocyclic carbene (NHC) ligands to the surface of 3.7nm palladium nanoparticles (PdNPs) can be unambiguously established by observation of Knight shift (KS) in the 13C ...resonance of the carbenic carbon. In order to validate this coordination, PdNPs with sizes ranging from 1.3 to 4.8nm were prepared by thermal decomposition or reduction with CO of a dimethyl NHC PdII complex. NMR studies after 13CO adsorption established that the KS shifts the 13C resonances of the chemisorbed molecules several hundreds of ppm to high frequencies only when the particle exceeds a critical size of around 2nm. Finally, the resonance of a carbenic carbon is reported to be Knight-shifted to 600ppm for 13C-labelled NHCs bound to PdNPs of 3.7nm. The observation of these very broad KS resonances was facilitated by using Car-Purcell-Meiboom-Gill (CPMG) echo train acquisition NMR experiments.
The cover picture shows dioxygen activation by CuII complexes supported by carboxylate‐containing ligands as structural and functional models of quercetin 2,4‐dioxygenase (2,4‐QD), highlighting the ...role of the carboxylate group in the structure and reactivity. The green fields, the blue sky, and the tree in the background symbolize molecular oxygen as a green and environmentally benign oxidant. Details are discussed in the article by Y.‐J. Sun, S. Itoh et al. on page 1845 ff (DOI: 10.1002/ejic.201601371). For more on the story behind the cover research, see the Cover Profile (DOI: 10.1002/ejic.201700245).
This cover feature shows the great potential of the ferrocene molecule for a custom‐made synthesis of ferrocene ligands, especially asymmetric disubstituted species bearing phosphine ligands and ...their corresponding group 11 metal complexes. These derivatives may be suitable for application in catalysis. Details are discussed in the article by M. D. Villacampa, M. C. Gimeno et al. on page 247 ff (DOI: 10.1002/ejic.201600929). For more on the story behind the cover research, see the Cover Profile (DOI: 10.1002/ejic.201601554).
The cover picture shows “Wanko Soba” (Iwate, Japan), an interesting dish of soba (buckwheat noodles). Each time that you take a mouthful of soba from a small dish, the maid refills it. The scheme ...illustrates the Ni‐catalyzed construction of chiral 1‐functionalized 6helicene derivatives on a multigram scale as a result of the stepwise study for scale up. This 10 g scale synthesis of helicene derivatives by 2+2+2 cycloaddition is the largest scale in this field. The enantiomerically pure 1‐6helicenols can be synthesized through an efficient optical resolution process via the corresponding camphanates. Furthermore, the development of a novel class of 6helicene‐based phosphinites and their preliminary investigation as asymmetric ligands are also described. Details are discussed in the Communication by T. Tsujihara, T. Kawano et al. on p. 4948 ff.
A palladium-catalyzed CH arylation of aliphatic amines with arylboronic esters is described, proceeding through a four-membered-ring cyclopalladation pathway. Crucial to the successful outcome of ...this reaction is the action of an amino-acid-derived ligand. A range of hindered secondary amines and arylboronic esters are compatible with this process and the products of the arylation can be advanced to complex polycyclic molecules by sequential CH activation reactions.
Although the cyclo-P6 complex (Cp*Mo)2(µ,η6:η6-P6) (1) was reported 30years ago, little is known about its chemistry. Herein, we report a high-yielding synthesis of 1, the complex 2, which contains ...an unprecedented cyclo-P10 ligand, and the reactivity of 1 towards the "naked" cations Cu+, Ag+, and Tl+. Besides the formation of the single oxidation products 3a,b which have a bisallylic distorted cyclo-P6 middle deck, the M(1)2+ complexes are described which show distorted square-planar (M=Cu(4a), Ag(4b)) or distorted tetrahedral coordinated (M=Cu(5)) M+ cations. The choice of solvent enabled control over the reaction outcome for Cu+, as proved by powder XRD and supported by DFT calculations. The reaction with Tl+ affords a layered two-dimensional coordination network in the solid state.
A palladium-catalyzed enantioselective CH functionalization of indoles was achieved with an axially chiral 2,2'-bipyridine ligand, thus providing the desired indol-3-acetate derivatives with up to ...98% ee. Moreover, the reaction protocol was also effective for asymmetric OH insertion reaction of phenols using alpha-aryl-alpha-diazoacetates. This represents the first successful application of bipyridine ligands with axial chirality in palladium-catalyzed carbene migratory insertion reactions.
The proteasome represents a validated drug target for the treatment of cancer, however, new types of inhibitors are required to tackle the development of resistant tumors. Current fluorescence-based ...screening methods suffer from low sensitivity and are limited to the detection of ligands with conventional binding profiles. In response to these drawbacks, a crystallographic screening procedure for the discovery of agents with a novel mode of action was utilized. The optimized workflow was applied to the screening of a focused set of compounds, resulting in the discovery of a beta1/beta2-specific sulfonamide derivative that noncovalently binds between subunits beta1 and beta2. The binding pocket displays significant differences in size and polarity between the immuno- and constitutive proteasome. The identified ligand thus provides valuable insights for the future structure-based design of subtype-specific proteasome inhibitors.
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