Co-crystalization and in vitro biological characterization of 5-Aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazole Hsp90 inhibitors

A potential therapeutic strategy for targeting cancer that has gained much interest is the inhibition of the ATP binding and ATPase activity of the molecular chaperone Hsp90. We have determined the structure of the human Hsp90α N-terminal domain in complex with a series of 5-aryl-4-(5-substituted-2-4-dihydroxyphenyl)-1,2,3-thiadiazoles. The structures provide the molecular details for the activity of these inhibitors. One of these inhibitors, ICPD 34, causes a structural change that affects a mobile loop, which adopts a conformation similar to that seen in complexes with ADP, rather than the conformation generally seen with the pyrazole/isoxazole-resorcinol class of inhibitors. Competitive binding to the Hsp90 N-terminal domain was observed in a biochemical assay, and these compounds showed antiproliferative activity and induced apoptosis in the HCT116 human colon cancer cell line. These inhibitors also caused induction of the heat shock response with the upregulation of Hsp72 and Hsp27 protein expression and the depletion of Hsp90 clients, CRAF, ERBB2 and CDK4, thus confirming that antiproliferative activity was through the inhibition of Hsp90. The presence of increased levels of the cleavage product of PARP indicated apoptosis in response to Hsp90 inhibitors. This work provides a framework for the further optimization of thiadiazole inhibitors of Hsp90. Importantly, we demonstrate that the thiadiazole inhibitors display a more limited core set of interactions relative to the clinical trial candidate NVP-AUY922, and consequently may be less susceptible to resistance derived through mutations in Hsp9

Conformational flexibility within the small domain of human serine racemase

Serine racemase (SR) is a pyridoxal 5′-phosphate (PLP)-containing enzyme that converts L-serine to D-serine, an endogenous co-agonist for the N-methyl-D-aspartate receptor (NMDAR) subtype of glutamate ion channels. SR regulates D-serine levels by the reversible racemization of L-serine to D-serine, as well as the catabolism of serine by α,β-elimination to produce pyruvate. The modulation of SR activity is therefore an attractive therapeutic approach to disorders associated with abnormal glutamatergic signalling since it allows an indirect modulation of NMDAR function. In the present study, a 1.89 Å resolution crystal structure of the human SR holoenzyme (including the PLP cofactor) with four subunits in the asymmetric unit is described. Comparison of this new structure with the crystal structure of human SR with malonate (PDB entry 3l6b) shows an interdomain cleft that is open in the holo structure but which disappears when the inhibitor malonate binds and is enclosed. This is owing to a shift of the small domain (residues 78–155) in human SR similar to that previously described for the rat enzyme. This domain movement is accompanied by changes within the twist of the central four-stranded β-sheet of the small domain, including changes in the φ–ψ angles of all three residues in the C-terminal β-strand (residues 149–151). In the malonate-bound structure, Ser84 (a catalytic residue) points its side chain at the malonate and is preceded by a six-residue β-strand (residues 78–83), but in the holoenzyme the β-strand is only four residues (78–81) and His82 has φ–ψ values in the α-helical region of the Ramachandran plot. These data therefore represent a crystallographic platform that enables the structure-guided design of small-molecule modulators for this important but to date undrugged target

Food Composition at Present: New Challenges

Food composition data is important for stakeholders and users active in the areas of food, nutrition and health. Newchallenges related to the quality of food composition data reflect the dynamic changes in these areas while the emerging technologies create new opportunities. These challenges and the impact on food composition data for the Mediterranean region were reviewed during the NUTRIMAD 2018 congress of the Spanish Society for Community Nutrition. Data harmonization and standardization, data compilation and use, thesauri, food classification and description, and data exchange are some of the areas that require new approaches. Consistency in documentation, linking of information between datasets, food matching and capturing portion size information suggest the need for new automated tools. Research Infrastructures bring together key data and services. The delivery of sustainable networks and Research Infrastructures in food, nutrition and health will help to increase access to and effective use of food composition data. EuroFIR AISBL coordinates experts and national compilers and contributes to worldwide efforts aiming to produce and maintain high quality data and tools. A Mediterranean Network that shares high quality food composition data is vital for the development of ambitious common research and policy initiatives in support of the Mediterranean Diet

Synthesis and electronic structure of the first cyaphide-alkynyl complexes

The novel complexes trans-[Ru(dppe)2(CCR)(CP)] (R = CO2Me, C6H4OMe), the first to incorporate cyaphide as part of a conjugated system, are obtained in facile manner. The electronic structure of these compounds is probed by X-ray, DFT and UV/Vis studies

Carbon dioxide activation by a uranium(III) complex derived from a chelating bis(aryloxide) ligand

The new dianionic ligand, C6H4{p-C(CH3)2C6H2Me2O−}2 (= p-Me2bp), featuring two aryloxide donors and a central arene ring, has been synthesized, and used to prepare the mixed-ligand U(III) compound, [U(Cp*)(p-Me2bp)] which exhibits an η6-interaction with the uranium center. Reductive activation of CO2 was investigated using [U(Cp*)(p-Me2bp)] in supercritical CO2, which gave a dinuclear uranium carbonate complex,{U(Cp*)(p-Me2bp)}2(μ-η1:η2-CO3), cleanly and selectively. Reactivity studies in conventional solvents using lower pressures of CO2 showed the formation of a rare U(IV) oxalate complex, {U(Cp*)(p-Me2bp)}2(μ-η2:η2-C2O2), alongside {U(Cp*)(p-Me2bp)}2(μ-η1:η2-CO3). The relative ratio of the latter two products is temperature dependent: at low temperatures (-78 ˚C) oxalate formation is favored, whilst at room temperature the carbonate is the dominant product. The U(IV) iodide, [U(Cp*)(p-Me2bp)I], was also synthesized and used as part of an electrochemical study, the results of which showed that [U(Cp*)(p-Me2bp)] has a UIV/UIII redox couple of −2.18 V vs FeCp2+/0 as well as an possible electrochemically accessible UIII/UII reduction process at −2.56 V vs FeCp2+/0

Trimerisation of carbon suboxide at a di-titanium centre to form a pyrone ring system

The reaction of the syn-bimetallic bis(pentalene)dititanium complex Ti2(μ:η5,η5-Pn†)2 (Pn† = C8H4(1,4-SiiPr3)2) 1 with carbon suboxide (O[double bond, length as m-dash]C[double bond, length as m-dash]C[double bond, length as m-dash]C[double bond, length as m-dash]O, C3O2) results in trimerisation of the latter and formation of the structurally characterised complex [{Ti2(μ:η5,η5-Pn†)2}{μ-C9O6}]. The trimeric bridging C9O6 unit in the latter contains a 4-pyrone core, a key feature of both the hexamer and octamer of carbon suboxide which are formed in the body from trace amounts of C3O2 and are, for example, potent inhibitors of Na+/K+-ATP-ase. The mechanism of this reaction has been studied in detail by DFT computational studies, which also suggest that the reaction proceeds via the initial formation of a mono-adduct of 1 with C3O2. Indeed, the carefully controlled reaction of 1 with C3O2 affords [Ti2(μ:η5,η5-Pn†)2 (η2-C3O2)], as the first structurally authenticated complex of carbon suboxide

Decarboxylative bromination of heteroarenes: initial mechanistic insights

After an initial report from our laboratory describing metal-free decarboxylative halogenation of various azaheteroarenes, we set out to investigate the possible mechanism by which this chemistry occurs. Evidence from this mechanistic investigation suggests that this chemistry occurs via a radical pathway, with 1HNMR studies suggesting the acidic substrates activate NBS

Rolling Back the Repo Safe Harbors

Recent decades have seen substantial expansion in exemptions from the Bankruptcy Code’s normal operation for repurchase agreements. These repos, which are equivalent to very short-term (often one-day) secured loans, are exempt from core bankruptcy rules such as the automatic stay that enjoins debt collection, rules against prebankruptcy fraudulent transfers, and rules against eve-of-bankruptcy preferential payment to favored creditors over other creditors. While these exemptions can be justified for United States Treasury securities and similarly liquid obligations backed by the full faith and credit of the United States government, they are not justified for mortgage-backed securities and other securities that could prove illiquid or unable to fetch their expected long-run value in a panic. The exemptions from baseline bankruptcy rules facilitate this kind of panic selling and, according to many expert observers, characterized and exacerbated the financial crisis of 2007-2009. The exemptions from normal bankruptcy rules should be limited to United States Treasury and similarly liquid securities, as they once were. The more recent expansion of the exemption to mortgage-backed securities should be reversed

Tah1 helix-swap dimerization prevents mixed Hsp90 co-chaperone complexes

Specific co-chaperone adaptors facilitate the recruitment of client proteins to the Hsp90 system. Tah1 binds the C-terminal conserved MEEVD motif of Hsp90, thus linking an eclectic set of client proteins to the R2TP complex for their assembly and regulation by Hsp90. Rather than the normal complement of seven α-helices seen in other tetratricopeptide repeat (TPR) domains, Tah1 unusually consists of the first five only. Consequently, the methionine of the MEEVD peptide remains exposed to solvent when bound by Tah1. In solution Tah1 appears to be predominantly monomeric, and recent structures have failed to explain how Tah1 appears to prevent the formation of mixed TPR domain-containing complexes such as Cpr6-(Hsp90)2-Tah1. To understand this further, the crystal structure of Tah1 in complex with the MEEVD peptide of Hsp90 was determined, which shows a helix swap involving the fifth α-helix between two adjacently bound Tah1 molecules. Dimerization of Tah1 restores the normal binding environment of the bound Hsp90 methionine residue by reconstituting a TPR binding site similar to that in seven-helix-containing TPR domain proteins. Dimerization also explains how other monomeric TPR-domain proteins are excluded from forming inappropriate mixed co-chaperone complexes

Quasi 1D Nanobelts from the Sustainable Liquid Exfoliation of Terrestrial Minerals for Future Martian based Electronics

The sky is the limit with regards to the societal impact nanomaterials can have on our lives. However, in this study we show that their potential is out of this world. The planet Mars has an abundant source of calcium sulfate minerals and in our work, we show that these deposits can be the basis of transformative nanomaterials to potentially support future space endeavors. Through a scalable eco-friendly liquid processing technique performed on two common terrestrial gypsum, our simple method presented a cost-efficient procedure to yield the commercially valuable intermediate phase of gypsum, known as bassanite. Through the liquid exfoliation of bassanite powders, suspensions of large aspect ratio anhydrite nanobelts with long-term stability were characterized through scanning electron microscopy and Raman spectroscopy. Transmission electron microscopy showed nanobelts to have a mesocrystal structure, with distinct nanoparticle constituents making up the lattice. Unexpectedly, anhydrite nanobelts had remarkable electronic properties, namely a bandgap that was easily tuned between semiconducting (~2.2 eV) and insulating (~4 eV) behaviors through dimensional control measured via atomic force microscopy. To demonstrate the application potential of our nanobelts; optoelectronic, electrochemical and nanocomposite measurements were made. For the hydrogen evolution reaction and mechanical reinforcement, selenite-based anhydrite nanobelts displayed superlative performances