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Chemical Science

Barry M Trost, James T Masters, Benjamin R Taft, Jean-Philip Lumb
We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, and sulfone acceptors generates stereodefined enynes in high yield. These compounds are engaged in an unprecedented, regio- and enantioselective copper-catalyzed conjugate reduction. The process exhibits a high functional group tolerance, and this enables the synthesis of a broad range of chiral products from simple, readily available alkyne precursors...
September 16, 2016: Chemical Science
Mei Ding, George E Cutsail, Daniel Aravena, Martín Amoza, Mathieu Rouzières, Pierre Dechambenoit, Yaroslav Losovyj, Maren Pink, Eliseo Ruiz, Rodolphe Clérac, Jeremy M Smith
Structural, spectroscopic and magnetic methods have been used to characterize the tris(carbene)borate compound PhB(MesIm)3Mn≡N as a four-coordinate manganese(IV) complex with a low spin (S = 1/2) configuration. The slow relaxation of the magnetization in this complex, i.e. its single-molecule magnet (SMM) properties, is revealed under an applied dc field. Multireference quantum mechanical calculations indicate that this SMM behavior originates from an anisotropic ground doublet stabilized by spin-orbit coupling...
September 1, 2016: Chemical Science
Xiaofan Ji, Hu Wang, Yang Li, Danyu Xia, Hao Li, Guping Tang, Jonathan L Sessler, Feihe Huang
We report here a new approach to creating diversiform copolymer-derived self-assembly morphologies that relies on macrocycle/anion recognition in aqueous media. This approach exploits the anion binding features of a water-soluble form of the so-called 'Texas-sized' molecular box. When this tetracationic receptor is added to an aqueous solution of an amphiphilic copolymer bearing tethered carboxylate anion substituents, binding occurs to form a macrocycle/polymer complex. As the concentration of the box-like receptor increases, the relative hydrophilic fraction of the copolymer complex likewise increases...
September 1, 2016: Chemical Science
Fereidoon Daryaee, Andrew Chang, Johannes Schiebel, Yang Lu, Zhuo Zhang, Kanishk Kapilashrami, Stephen G Walker, Caroline Kisker, Christoph A Sotriffer, Stewart L Fisher, Peter J Tonge
Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection...
September 1, 2016: Chemical Science
Vanessa Pierroz, Riccardo Rubbiani, Christian Gentili, Malay Patra, Cristina Mari, Gilles Gasser, Stefano Ferrari
Photodynamic therapy (PDT) is an attractive, complementary medical technique to chemotherapy. Among the different photosensitizers (PSs) employed, Ru(ii) polypyridyl complexes were found to be valid substitutes to porphyrin-based or phthalocyanine-based PSs. Here, we confirm that one such complex, namely [Ru(bipy)2-dppz-7-methoxy][PF6]2 (Ru65), which localizes in the nucleus of various cancer and normal cells, displays cytotoxicity only upon UV-A irradiation. Importantly, we disclose the molecular mechanism of the UV-A mediated cytotoxic action of Ru65...
August 16, 2016: Chemical Science
Sarah J Smith, Robert J Radford, Rohit H Subramanian, Brandon R Barnett, Joshua S Figueroa, F Akif Tezcan
Given the prevalent role of α-helical motifs on protein surfaces in mediating protein-protein and protein-DNA interactions, there have been significant efforts to develop strategies to induce α-helicity in short, unstructured peptides to interrogate such interactions. Toward this goal, we have recently introduced hybrid metal coordination motifs (HCMs). HCMs combine a natural metal-binding amino acid side chain with a synthetic chelating group that are appropriately positioned in a peptide sequence to stabilize an α-helical conformation upon metal coordination...
August 1, 2016: Chemical Science
D K O'Flaherty, A Patra, Y Su, F P Guengerich, M Egli, C J Wilds
DNA lesions that elude repair may undergo translesion synthesis catalyzed by Y-family DNA polymerases. O (4)-Alkylthymidines, persistent adducts that can result from carcinogenic agents, may be encountered by DNA polymerases. The influence of lesion orientation around the C4-O (4) bond on processing by human DNA polymerase η (hPol η) was studied for oligonucleotides containing O (4)-methylthymidine, O (4)-ethylthymidine, and analogs restricting the O (4)-methylene group in an anti-orientation. Primer extension assays revealed that the O (4)-alkyl orientation influences hPol η bypass...
August 1, 2016: Chemical Science
David T Krist, Sungjin Park, Galyah H Boneh, Sarah E Rice, Alexander V Statsyuk
Homologous to E6AP Carboxyl Terminus E3 ubiquitin ligases (HECT, ~28 known) are genetically implicated in cancer, neurological, hypertensive, and autoimmune disorders, and are potential drug targets to treat these diseases. The major bottleneck in the field of HECT E3s is a lack of simple assays to quantify the enzymatic activity of these enzymes in the presence of small molecules. Typical assays require E1, E2, HECT E3, ubiquitin (Ub), ATP and additional reagents to detect the resulting free poly-ubiquitin chains...
August 1, 2016: Chemical Science
Chung-Yon Lin, Michael W Giuliano, Bryan D Ellis, Scott J Miller, Eric V Anslyn
High-throughput screening for asymmetric catalysts has stimulated an interest in optically-based enantiomeric-excess (ee) sensors, primarily for their improved time and cost efficiency when compared to the standard HPLC analysis. We present herein substituent-effect studies on a recently reported Zn(II) multicomponent assembly that is used for chiral, secondary alcohol ee detemination. The systematic altering of assemblies formed from select substituted pyridyl ligands pointed to the conclusion that steric effects dominate the mode of interaction at the pyridyl 3- and 6- positions...
July 1, 2016: Chemical Science
Benjamin H Rotstein, Lu Wang, Richard Y Liu, Jon Patteson, Eugene E Kwan, Neil Vasdev, Steven H Liang
Synthesis of non-activated electron-rich and sterically hindered (18)F-arenes remains a major challenge due to limitations of existing radiofluorination methodologies. Herein, we report on our mechanistic investigations of spirocyclic iodonium(III) ylide precursors for arene radiofluorination, including their reactivity, selectivity, and stability with no-carrier-added [(18)F]fluoride. Benchmark calculations at the G2[ECP] level indicate that pseudorotation and reductive elimination at iodine(III) can be modeled well by appropriately selected dispersion-corrected density functional methods...
July 1, 2016: Chemical Science
Mary C Andorfer, Hyun June Park, Jaylie Vergara-Coll, Jared C Lewis
RebH variants capable of chlorinating substituted indoles ortho-, meta-, and para- to the indole nitrogen were evolved by directly screening for altered selectivity on deuterium-substituted probe substrates using mass spectrometry. This systematic approach allowed for rapid accumulation of beneficial mutations using simple adaptive walks and should prove generally useful for altering and optimizing the selectivity of C-H functionalization catalysts. Analysis of the beneficial mutations showed that structure-guided selection of active site residues for targeted mutagenesis can be complicated either by activity/selectivity tradeoffs that reduce the possibility of detecting such mutations or by epistatic effects that actually eliminate the benefits of a mutation in certain contexts...
June 1, 2016: Chemical Science
Rudolf Wedmann, Constantin Onderka, Shengwei Wei, István András Szijártó, Jan Lj Miljkovic, Aleksandra Mitrovic, Mike Lange, Sergey Savitsky, Pramod Kumar Yadav, Roberta Torregrossa, Ellen G Harrer, Thomas Harrer, Isao Ishii, Maik Gollasch, Mark E Wood, Erwan Galardon, Ming Xian, Matthew Whiteman, Ruma Banerjee, Milos R Filipovic
Hydrogen sulfide (H2S) has emerged as a signalling molecule capable of regulating several important physiological functions such as blood pressure, neurotransmission and inflammation. The mechanisms behind these effects are still largely elusive and oxidative posttranslational modification of cysteine residues (protein persulfidation or S-sulfhydration) has been proposed as the main pathway for H2S-induced biological and pharmacological effects. As a signalling mechanism, persulfidation has to be controlled...
May 25, 2016: Chemical Science
Arun K Ghosh, Bhavanam Sekhara Reddy, Yu-Chen Yen, Emilio Cardenas, Kalapala Venketeswara Rao, Deborah Downs, Xiangping Huang, Jordan Tang, Andrew D Mesecar
Design, synthesis and evaluation of very potent and selective β-Secretase 2 (memapsin 1, BACE 2) inhibitors are described. The inhibitors were designed specifically to interact with the S2'-site of β-secretase 2 to provide >170,000-fold selectivity over β-secretase (BACE 1) and >15,000-fold selectivity over cathepsin D. BACE 2 is implicated in Type 2 diabetes. The studies serve as an important guide to selective BACE 2 inhibitors.
May 1, 2016: Chemical Science
Jéssica Rodríguez, Jesús Mosquera, Rebeca García-Fandiño, M Eugenio Vázquez, José L Mascareñas
We report the rational design of a DNA-binding peptide construct composed of the DNA-contacting regions of two transcription factors (GCN4 and GAGA) linked through an AT-hook DNA anchor. The resulting chimera, which represents a new, non-natural DNA binding motif, binds with high affinity and selectivity to a long composite sequence of 13 base pairs (TCAT-AATT-GAGAG).
May 1, 2016: Chemical Science
Brandon C Knott, Michael F Crowley, Michael E Himmel, Jochen Zimmer, Gregg T Beckham
The processive cycle of the bacterial cellulose synthase (Bcs) includes the addition of a single glucose moiety to the end of a growing cellulose chain followed by the translocation of the nascent chain across the plasma membrane. The mechanism of this translocation and its precise location within the processive cycle are not well understood. In particular, the molecular details of how a polymer (cellulose) whose basic structural unit is a dimer (cellobiose) can be constructed by adding one monomer (glucose) at a time are yet to be elucidated...
May 1, 2016: Chemical Science
Mihoko Yamada, Kenneth D Karlin, Shunichi Fukuzumi
Benzene was hydroxylated with hydrogen peroxide (H2O2) in the presence of catalytic amounts of copper complexes in acetone to yield phenol at 298 K. At higher temperature, phenol was further hydroxylated with H2O2 by catalysis of copper complexes to yield p-benzoquinone. The kinetic study revealed that the rate was proportional to concentrations of benzene and H2O2, but to the square root of concentration of a copper(II) complex ([Cu(tmpa)](2+): tmpa = tris(2-pyridylmethyl)amine). The addition of a spin trapping reagent resulted in formation of a spin adduct of hydroperoxyl radical (HO2 (•)), as observed by EPR spectroscopy, inhibiting phenol formation...
April 1, 2016: Chemical Science
Cristina Penas, José L Mascareñas, M Eugenio Vázquez
Rational modification of a natural RNA-binding peptide with a lanthanide EDTA chelator, and a phenanthroline ligand yields a highly selective luminescent sensor. The sensing mechanism relies on the RNA-triggered folding of the peptide into a β-hairpin, which promotes the coordination of the phenanthroline sensitizer, and the efficient sensitization of complexed lanthanide ions.
April 1, 2016: Chemical Science
Aiman Sadaf, Jonas S Mortensen, Stefano Capaldi, Elena Tikhonova, Parameswaran Hariharan, Orquidea de Castro Ribeiro, Claus J Loland, Lan Guan, Bernadette Byrne, Pil Seok Chae
Membrane proteins are amphipathic bio-macromolecules incompatible with the polar environments of aqueous media. Conventional detergents encapsulate the hydrophobic surfaces of membrane proteins allowing them to exist in aqueous solution. Membrane proteins stabilized by detergent micelles are used for structural and functional analysis. Despite the availability of a large number of detergents, only a few agents are sufficiently effective at maintaining the integrity of membrane proteins to allow successful crystallization...
March 1, 2016: Chemical Science
Phoom Chairatana, Hiutung Chu, Patricia A Castillo, Bo Shen, Charles L Bevins, Elizabeth M Nolan
Human α-defensin 6 (HD6) is a unique peptide of the defensin family that provides innate immunity in the intestine by self-assembling to form high-order oligomers that entrap bacteria and prevent host cell invasion. Here, we report critical steps in the self-assembly pathway of HD6. We demonstrate that HD6 is localized in secretory granules of small intestinal Paneth cells. HD6 is stored in these granules as an 81-residue propeptide (proHD6), and is recovered from ileal lumen as a 32-residue mature peptide...
March 1, 2016: Chemical Science
Carl-Johan Carling, Jason Olejniczak, Alexandra Foucault-Collet, Guillaume Collet, Mathieu L Viger, Viet Anh Nguyen Huu, Brendan M Duggan, Adah Almutairi
We introduce a means of efficiently photo-uncaging active compounds from amino-1,4-benzoquinone in aqueous environments. Aqueous photochemistry of this photocage with one-photon red light is typically not efficient unless the photocaged molecules are allowed to assemble into nanoparticles. A variety of biologically active molecules were functionalized with the photocage and subsequently formulated into water-dispersible nanoparticles. Red light irradiation through various mammalian tissues achieved efficient photo-uncaging...
March 2016: Chemical Science
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