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Ez-Zoubir M.,Ecole Nationale Superieure de Chimie de Paris | Brown J.A.,Medicines Research Center | Ratovelomanana-Vidal V.,Ecole Nationale Superieure de Chimie de Paris | Michelet V.,Ecole Nationale Superieure de Chimie de Paris
Journal of Organometallic Chemistry | Year: 2011

The efficiency of an Ir(I)/HI system has been studied. The association of hydroiodic acid with iridium has been tested in the catalytic hydroiodination of alkynes. The use of [Ir(cod)Cl]2 dimer led to clean hydroiodination reactions and afforded the corresponding vinyliodides as a mixture of derivatives, where the Markovnikov type adduct was found to be the major product (80/20 to 93/7 ratio), in good yields. The mechanism was investigated and two main pathways seemed to be involved, one based on an initial oxidative addition of HI to the Ir(I) complex and the other one based on a π-activation of the alkyne moiety. The corresponding vinyliodides were engaged in Pd-catalyzed cross-coupling (Sonogashira and Suzuki-Miyaura) reactions under organoaqueuous conditions. © 2010 Elsevier B.V. All rights reserved.

Yang H.-T.,UK National Institute for Medical Research | Papoutsopoulou S.,UK National Institute for Medical Research | Belich M.,UK National Institute for Medical Research | Belich M.,Medicines Research Center | And 6 more authors.
Molecular and Cellular Biology | Year: 2012

The role of IκB kinase (IKK)-induced proteolysis of NF-κB1 p105 in innate immune signaling was investigated using macrophages from Nfkb1SSAA/SSAA mice, in which the IKK target serines on p105 are mutated to alanines. We found that the IKK/p105 signaling pathway was essential for TPL-2 kinase activation of extracellular signal-regulated kinase (ERK) mitogen-activate protein (MAP) kinase and modulated the activation of NF-κB. The Nfkb1SSAA mutation prevented the agonist-induced release of TPL-2 from its inhibitor p105, which blocked activation of ERK by lipopolysaccharide (LPS), tumor necrosis factor (TNF), CpG, tripalmitoyl-Cys-Ser-Lys (Pam3CSK), poly(I · C), flagellin, and R848. The Nfkb1SSAA mutation also prevented LPS-induced processing of p105 to p50 and reduced p50 levels, in addition to decreasing the nuclear translocation of RelA and cRel. Reduced p50 in Nfkb1SSAA/SSAA macrophages significantly decreased LPS induction of the IκBξ-regulated Il6 and Csf2 genes. LPS upregulation of Il12a and Il12b mRNAs was also impaired although specific blockade of TPL-2 signaling increased expression of these genes at late time points. Activation of TPL-2/ERK signaling by IKK-induced p105 proteolysis, therefore, induced a negative feedback loop to downregulate NF-κB-dependent expression of the proinflammatory cytokine interleukin-12 (IL-12). Unexpectedly, TPL-2 promoted soluble TNF production independently of IKK-induced p105 phosphorylation and its ability to activate ERK, which has important implications for the development of anti-inflammatory drugs targeting TPL-2. © 2012, American Society for Microbiology.

Marshall L.J.,University of St. Andrews | Cable K.M.,Medicines Research Center | Botting N.P.,University of St. Andrews
Tetrahedron Letters | Year: 2010

The preparation of bis-protected phloroglucinol derivatives from a range of protected resorcinol substrates is presented. Functionalization was achieved via a two-step, one-pot iridium-catalyzed C-H activation/borylation/oxidation protocol. Our system gave high conversions to the arylboronic esters and good yields of the desired phenols following subsequent oxidation. A range of common protecting group categories was studied including alkyl, silyl, ether and ester. © 2010 Elsevier Ltd. All rights reserved.

Poingdestre S.-J.,University of Oxford | Goodacre J.D.,Medicines Research Center | Weller A.S.,University of Oxford | Willis M.C.,University of Oxford
Chemical Communications | Year: 2012

The use of the electron-rich diphosphine ligand, dcpe, allows the efficient and highly linear selective hydroacylative coupling of aldehydes, including aryl examples, with a range of alkynes. © 2012 The Royal Society of Chemistry.

Taddese B.,University of Essex | Simpson L.M.,University of Essex | Wall I.D.,Medicines Research Center | Blaney F.E.,Memprot Consulting | Reynolds C.A.,University of Essex
Methods in Enzymology | Year: 2013

The most significant advance in modeling GPCR active states has been the β2-adrenergic receptor-Gs complex as this essentially transforms active-state modeling into homology modeling. Various different molecular dynamics-based approaches for modeling active states are presented, and a number of key applications discussed. These simulations have given insights into the activation pathway, conformational changes, dimerization, hydration, the ionic lock, ligand binding, protonation, and sodium binding. Crystallography and simulations have shown that the presence of agonist alone is unlikely to be sufficient to form the active state and that restraints applied to the G protein-binding region are required. The role of various microswitches in activation is discussed, including the controversial rotamer toggle switch. The importance of explicitly simulating experimental molecular probes to understand activation is highlighted, along with the need to ensure that such molecules are well parameterized. Approaches to loop modeling are discussed. We argue that the role of successful virtual screening against active models should not be overestimated as the main conformational changes on activation occur in the intracellular region. © 2013 Elsevier Inc.

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