Identification of glycolytic proteins as binding partners of Bri2 BRICHOS domain.

Human integral membrane protein 2B (ITM2B or Bri2) is a member of the BRICHOS family, that can attenuate Aβ pathology in the brain. As a result, the identification of novel Bri2 BRICHOS client proteins has been sought to help elucidate signaling pathways and the potential identification of novel therapeutic targets. To identify Bri2 BRICHOS interacting partners, we carried out a 'protein fishing' experiment using recombinant human (rh) Bri2 BRICHOS-coated magnetic particles, in combination with proteomic analysis on cytosolic and membrane fractions of cortical homogenates from C57BL/6 J WT mouse.

Multifunctional Catalysts in the Asymmetric Mannich Reaction of Malononitrile with -Phosphinoylimines: Coactivation by Halogen Bonding versus Hydrogen Bonding.

A multifunctional (noncovalent) catalyst containing halogen-bond donor, hydrogen-bond donor, and Lewis basic sites was developed and applied in an enantioselective Mannich reaction between malononitrile and diphenylphosphinoyl-protected aldimine affording products in high yields (up to 98%) and moderate to high enantiomeric purities (ee up to 89%). Typically, noncovalent catalysts rely on several weak interactions to activate the substrate, with one or two of these giving the most notable contribution to activation. In this instance, instead of the initially proposed coactivation by halogen bonding, it was revealed that hydrogen bonding plays a key role in determining the enantioselectivity.

Asymmetric organocatalytic Michael addition of cyclopentane-1,2-dione to alkylidene oxindole.

An asymmetric Michael reaction between cyclopentane-1,2-dione and alkylidene oxindole was studied in the presence of a multifunctional squaramide catalyst. Michael adducts were obtained in high enantioselectivities and in moderate diastereoselectivities.

Asymmetric Chemoenzymatic One-Pot Synthesis of α-Hydroxy Half-Esters.

A new chemoenzymatic one-pot strategy has been developed for the synthesis of α-hydroxy half-esters containing consecutive quaternary and tertiary stereocenters using asymmetric cascade catalysis. In this study, an asymmetric Ca-catalyzed [2,3]-Wittig rearrangement reaction was proven to be suitable for a combination with porcine liver esterase-mediated hydrolysis resulting in the enhanced enantiomeric purity of the obtained products in a one-pot synthesis compared to the stepwise method.

Enantioselective Michael addition to vinyl phosphonates hydrogen bond-enhanced halogen bond catalysis.

An asymmetric Michael addition of malononitrile to vinyl phosphonates was accomplished by hydrogen bond-enhanced bifunctional halogen bond (XB) catalysis. NMR titration experiments were used to demonstrate that halogen bonding, with the support of hydrogen-bonding, played a key role in the activation of the Michael acceptors through the phosphonate group. This is the first example of the use of XBs for the activation of organophosphorus compounds in synthesis.

Designed whole-cell-catalysis-assisted synthesis of 9,11-secosterols.

A method for the synthesis of 9,11-secosteroids starting from the natural corticosteroid cortisol is described. There are two key steps in this approach, combining chemistry and synthetic biology. Stereo- and regioselective hydroxylation at C9 (steroid numbering) is carried out using whole-cell biocatalysis, followed by the chemical cleavage of the C-C bond of the vicinal diol.

Enantioselective Organocatalytic Michael Addition to Unsaturated Indolyl Ketones.

An efficient enantioselective organocatalytic method for the synthesis of -alkylated indoles with α-branched alkyl substituents from the corresponding unsaturated indolyl ketones via a Michael addition has been developed. The resulting products were obtained in high enantioselectivities and in good yields. Various nucleophiles (nitroalkanes, malononitrile, malonic esters) can be used.

A phenotypic approach to probing cellular outcomes using heterobivalent constructs.

Various conjugation techniques are used to affect the intracellular delivery of bioactive small molecules. However, the ability to track changes in the phenotype when applying these tools remains poorly studied. We addressed this issue by having prepared a focused library of heterobivalent constructs based on Rho kinase inhibitor HA-100.

Gly188Arg substitution eliminates substrate inhibition in arachidonate 11R-lipoxygenase.

Lipoxygenases (LOXs) are dioxygenases that catalyze the oxygenation of polyunsaturated fatty acids to hydroperoxyl derivates. These products are precursors for different lipid mediators which are associated with pathogenesis of various diseases such as asthma, atherosclerosis and cancer. Several LOXs suffer from substrate inhibition, a potential regulatory mechanism, yet it is unclear what is the cause of this phenomenon.

Formation and trapping of the thermodynamically unfavoured inverted-hemicucurbit[6]uril.

Formation of inverted-cis-cyclohexanohemicucurbit[6]uril (i-cis-cycHC[6]), with up to 33% isolated yield, can be induced at the expense of thermodynamically favoured cis-cycHC[6]. Reaction selectivity is governed by the solution-based template-aided dynamic combinatorial chemistry and continuous precipitation of the formed macrocycles. Different binding affinities of three diastereomeric cycHC[6]s with trifluoroacetic acid is demonstrated.

[2,3]-Wittig Rearrangement as a Formal Asymmetric Alkylation of α-Branched Ketones.

The enantioselective [2,3]-Wittig rearrangement of cinnamyloxycyclopentanone derivatives was performed in the presence of a Cinchona-based primary amine. The described method provides synthetically valuable α-hydroxy ketones with quaternary stereogenic centers in excellent enantiomeric purities. Relying on the X-ray crystal structure of the product and the DFT calculations, we propose that the rearrangement is promoted by an intramolecular hydrogen bond between the substrate and the catalyst.

Tunable chiral triazole-based halogen bond donors: assessment of donor strength in solution with nitrogen-containing acceptors.

Strong halogen bond (XB) donors are needed for the activation of neutral substrates. We demonstrate that XB donor properties of iodo-triazoles can be significantly enhanced by quaternization in combination with varying the counterion and aromatic substituent, exemplified by association constants with quinuclidine as high as 1.1 × 10 M.

Halo-1,2,3-triazolium Salts as Halogen Bond Donors for the Activation of Imines in Dihydropyridinone Synthesis.

In the past decade halogen bond (XB) catalysis has gained considerable attention. Halo-triazoles are known XB donors, yet few examples detail their use as catalysts. As a continuation of our previous work the catalytic properties of substituted enantiomerically pure halo-triazolium salts were explored in the reaction between an imine and Danishefsky's diene leading to the formation of dihydropyridinone.

Site-Selective and Stereoselective C-H Functionalization of N-Cyclopropylamides via a Directed Remote Metalation Strategy.

A new methodology for site-selective and stereoselective C-H functionalization of aminocyclopropanes via directed remote lithiation has been developed. Treatment of N-directing group (DG = pivaloyl, tetramethylsuccinimidoyl) arylcyclopropanes with t-BuLi results in a clean β-lithiation and, following quench with electrophiles, leads to a range of cyclopropane derivatives. Sequential double lithiation-methylation to give a dimethylated cyclopropane has been achieved.

Size-Control by Anion Templating in Mechanochemical Synthesis of Hemicucurbiturils in the Solid State.

Self-organization is one of the most intriguing phenomena of chemical matter. While the self-assembly of macrocycles and cages in dilute solutions has been extensively studied, it remains poorly understood in solvent-free environments. Provided here is the first example of using anionic templates to achieve selective assembly of differently-sized macrocycles in a solvent-free system.

Copper(I)-binding properties of de-coppering drugs for the treatment of Wilson disease. α-Lipoic acid as a potential anti-copper agent.

Wilson disease is an autosomal recessive genetic disorder caused by loss-of-function mutations in the P-type copper ATPase, ATP7B, which leads to toxic accumulation of copper mainly in the liver and brain. Wilson disease is treatable, primarily by copper-chelation therapy, which promotes copper excretion. Although several de-coppering drugs are currently available, their Cu(I)-binding affinities have not been quantitatively characterized.

Synthesis of γ-keto sulfones by copper-catalyzed oxidative sulfonylation of tertiary cyclopropanols.

Tertiary cyclopropanols undergo ring-opening oxidative sulfonylation to afford γ-keto sulfones when reacting with sulfinate salts in the presence of a copper(ii) acetate catalyst and an oxidant (tert-butyl hydroperoxide or atmospheric oxygen). Various fluoroalkyl, aryl and alkyl sulfinate salts are successfully employed as sulfonylation reagents, affording the corresponding sulfones in up to 94% yields. The experimental protocol is mild and tolerates a number of functionalities in the cyclopropanol substrate.

A PDZ-like domain mediates the dimerization of 11R-lipoxygenase.

Lipoxygenases (LOXs), participating in inflammatory processes and cancer, are a family of enzymes with high potential as drug targets. Various allosteric effects have been observed with different LOX isozymes (e.g.

Two-step conversion of carboxylic esters into distally fluorinated ketones via ring cleavage of cyclopropanol intermediates: application of sulfinate salts as fluoroalkylating reagents.

Tertiary cyclopropanols easily available from carboxylic esters have been used in the synthesis of distally fluorinated ketones. Cyclopropane ring cleavage reactions in methanol with aqueous tert-butyl hydroperoxide in the presence of a copper(ii) acetate catalyst and sodium triflinate (Langlois reagent) afford β-trifluoromethyl ketones in 16-74% isolated yields. Sodium triflinate serves as a precursor of reactive trifluoromethyl copper species, enabling ring-opening trifluoromethylation, as evidenced by mechanistic studies.

Synthesis and Characterisation of Chiral Triazole-Based Halogen-Bond Donors: Halogen Bonds in the Solid State and in Solution.

A general platform for the synthesis of various chiral halogen-bond (XB) donors based on the triazole core and the characterisation of factors that influence the strength of the halogen bond in the solid state and in solution are reported. The characterisation of XB donors in the solid state by X-ray crystallography and in solution by H NMR titration can be used to aid the design of new XB donors. We describe the first example of a XB between iodotriazoles and thioureas in solution.

Two Catalytic Methods of an Asymmetric Wittig [2,3]-Rearrangement.

Two different approaches for asymmetric catalytic Wittig [2,3]-rearrangement were developed. Allyloxymalonate derivatives were converted into homoallyl alcohols via organocatalytic or Ca-catalyzed pathways in moderate to high enantioselectivities.

Asymmetric Organocatalytic Wittig [2,3]-Rearrangement of Oxindoles.

A highly enantioselective organocatalytic [2,3]-rearrangement of oxindole derivatives is presented. The reaction was catalyzed by squaramide, and this provides access to 3-hydroxy 3-substituted oxindoles in high enantiomeric purities.

A conserved π-cation and an electrostatic bridge are essential for 11R-lipoxygenase catalysis and structural stability.

Lipoxygenases (LOXs) are lipid-peroxidizing enzymes that consist of a regulatory calcium- and membrane-binding PLAT (polycystin-1, lipoxygenase, α-toxin) domain and a catalytic domain. In a previous study, the crystal structure of an 11R-LOX revealed a conserved π-cation bridge connecting these two domains which could mediate the regulatory effect of the PLAT domain to the active site. Here we analyzed the role of residues Trp107 and Lys172 that constitute the π-cation bridge in 11R-LOX along with Arg106 and Asp173-a potential salt bridge, which could also contribute to the inter-domain communication.

Template-controlled synthesis of chiral cyclohexylhemicucurbit[8]uril.

Enantiomerically pure cyclohexylhemicucurbit[8]uril (cycHC[8]), possessing a barrel-shaped cavity, has been prepared in high yield on a gram scale from either (R,R,N,N')-cyclohex-1,2-diylurea and formaldehyde or cycHC[6]. In either case, a dynamic covalent library is first generated from which the desired cycHC can be amplified using a suitable anion template.