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Viewing upcoming talks containing the keyword: 13
Proline conformation in intrinsically unfolded proteins : sense or nonsense? (Video Conference from Edinburgh)
Speaker: Guy Lippens (University of Lille)
The conformational state of distinct prolines can determine the folding of a protein but equally other biological processes when coupled to a conformation sensitive secondary reaction. The importance of proline conformation is underscored by the interaction of many of those proteins with different prolyl cis/trans isomerases.
We will present our results on the proline conformation in two examples, the neuronal protein Tau and the non-structural protein NS5A of the HCV virus. For Tau, a number of molecular diseases including Alzheimer’s disease (AD) and Traumatic Brain injury (TBI) were recently qualified as “cistauois” (Kondo et al. 2015) and would imply a cis conformation for the pThr213-Pro232 prolyl bond. For NS5A, the molecular interaction between NS5A and the host cyclophilin is essential for the viral RNA replication, and implies a small motif centered on a particular proline residue (Dujardin et al., 2015).
Using NMR spectroscopy as an analytical tool, we have investigated the conformational aspects of the different prolines in both systems, and will discuss the possible interaction with prolyl cis/trans isomerases such as Pin1and FKBP52 (Giustiniani et al., PNAS 2014).
Dujardin et al., A Proline-Tryptophan Turn in the Intrinsically Disordered Domain 2 of NS5A Protein Is Essential for Hepatitis C Virus RNA Replication. , J Biol Chem. 2015 Jul 31;290(31):19104-20.
Kondo et al., Antibody against early driver of neurodegeneration cis P-tau blocks brain injury and tauopathy., Nature. 2015 Jul 23;523(7561):431-6.
Giustiniani et al., Immunophilin FKBP52 induces Tau-P301L filamentous assembly in vitro and modulates its activity in a model of tauopathy. Proc Natl Acad Sci U S A. 2014 Mar 25;111(12):4584-9.
On: October 7, 2015 From: 15h30 To: 16h30View talk
Molecular Oncology - Past, present and future of anti-cancer drug discovery illustrated with the story of EGFR inhibitors
Speaker: Mike Waring (University of Newcastle)
Molecular Oncology - Past, present and future of anti-cancer drug discovery illustrated with the story of EGFR inhibitors
Prof. Michael J. Waring
Northern Institute for Cancer Research, School of Chemistry, Bedson Building, Newcastle University, Newcastle upon Tyne, NE1 7RU, United Kingdom.
Formerly of AstraZeneca Oncology Innovative Medicines, Mereside, Alderley Park, Macclesfield, Cheshire, SK10 4TG, United Kingdom
Small molecule inhibitors of the Epidermal Growth Factor Receptor (EGFR) tyrosine kinase such as gefitinib and erlotinib have been employed successfully in the treatment of non-small cell lung cancer (NSCLC) patients harboring an activating mutation (EGFRm+). However, resistance to these inhibitors in the form of additional mutations in the kinase domain such as T790M is emerging as a growing clinical issue. This presentation will describe the discovery of AZD9291, an orally bioavailable, irreversible EGFR inhibitor of both the resistance (NCI-H1975, cell phosphorylation IC50 <0.025 mM) and activating mutations (PC9, cell phosphorylation IC50 <0.025 mM) that also spares inhibition of the wild type form of the receptor (A431, cell phosphorylation IC50 >0.5 mM). Wild type EGFR inhibition is believed to drive the observed dose limiting toxicities (such as skin rash and diarrhoea) for these first generation therapies in the clinic. This presentation will disclose the medicinal chemistry program that led to the identification of AZD9291 and details of significant in vivo oral activity in pre-clinical xenograft models (including tumour regression in the L858R/T790M double mutant setting at a dose of 5 mpk). The pre-clinical findings from this work strongly supported selection of AZD9291 as a clinical candidate, and first dose in man was achieved with AZD9291 in March 2013.
L858R/T790M Double Mutant (resistance) cell IC50 (mM)
EGFRm+ Single Mutant (activating) cell IC50 (mM)
EGFR Wild Type cell IC50 (mM)
Aqueous solubility, (in salt form) (pH=6.8, mg/mL)
Double Mutant efficacy (% TGI at 5mpk PO QD for 14 days)
On: October 14, 2015 From: 15h30 To: 16h30View talk
Influencing the Properties of Lanthanide Single-Molecule Magnets with the Devilâ€™s Elements (Video Conference from Edinburgh)
Speaker: Richard Layfield (Manchester)
Single-Molecule Magnets (SMMs) are a type of molecular nanomagnet characterized by the ability to
display magnetic hysteresis that is molecular in origin, and by an effective energy barrier to reversal of the
magnetization. In addition to the fundamental interest in SMMs, the electron-transport properties of these materials
have stimulated considerable interest by virtue of their applications as components in molecular spintronic devices.
The overwhelming majority of SMMs contain ligands based on 2p elements, with N- and O-donor
ligands being particularly prevalent, but with organometallic ligands now growing in popularity. An
alternative strategy with hugely under-exploited potential for influencing the properties of SMMs is to
use ligands with heavier p-block elements as the donor atoms. Indeed, molecular magnets containing,
for example, heavier pnictogen donor ligands are extremely rare. Heavier p-block elements offer more
diffuse valence orbitals than their lighter congeners, which introduces possibilities for studying the
impact of small but potentially significant increases in covalent contributions to the predominantly
ionic lanthanide-ligand bonds.
In this lecture, the dynamic magnetic properties of a series of dysprosium ring systems with various
types of phosphorus- and arsenic-donor ligand (Figure 1) will be described. Our experimental studies
are supported by ab initio calculations, which have enabled us to construct a simple model for the
magnetic anisotropy and magnetization relaxation mechanisms in our SMMs. The theoretical model
also provides insight into how SMMs with larger anisotropy barriers may be designed, and selected
new systems with antimony- and selenium-based ligands will also be presented.
During the course of our work on molecular magnets we have also done some unusual catalysis by
mistake; twice. Selected results will be presented.
Acknowledgements: Financial support from the ERC, the EPSRC, EU MSC Actions, and the Royal
Society is gratefully acknowledged.
Selected references:  D. N. Woodruff, R. E. P. Winpenny, R. A. Layfield, Chem. Rev. 2013, 113, 5110.  R. A.
Layfield, Organometallics 2014, 33, 1084.  T. Pugh, A. Kerridge, R. A. Layfield, Angew. Chem. Int. Ed. 2015, 54, 4255.
 T. Pugh. L. Ungur, F. Tuna, E. J. L. McInnes, D. Collison, L. F. Chibotaru, R. A. Layfield Nat. Commun. 2015, 6, 7492.
 T. Pugh, V. Vieru, L. F. Chibotaru R. A. Layfield, manuscript submitted.
On: October 21, 2015 From: 15h30 To: 16h30View talk
Speaker: Sir Fraser Stoddart (Northwestern)
The Nature of the Mechanical Bond
Department of Chemistry, Northwestern University, Evanston, IL 60208
The emergence of the mechanical bond during the past 25 years is giving chemistry a fillip in more ways than one. While its arrival on the scene is already impacting materials science and molecular nanotechnology, it is also providing a new lease of life to chemical synthesis where mechanical bond formation occurs as a consequence of the all-important templation orchestrated by molecular recognition and self-assembly processes. The way in which covalent bond formation activates noncovalent bonding interactions, switching on molecular recognition that leads to self-assembly and the template-directed synthesis of mechanically interlocked molecules—of which the so-called catenanes and rotaxanes may be regarded as the prototypes—has introduced a level of integration into chemical synthesis that has not previously been attained jointly at the supramolecular and molecular levels. The challenge now is to carry this level of integration, already achieved during molecular synthesis, beyond relatively small molecules into the realms of precisely functionalized extended molecular structures and aggregated superstructures that perform functions in a collective manner as the key sources of instruction, activation and performance in multi-component integrated devices.
Following a general introduction to the mechanical bond, my lecture will highlight the following topics – namely (1) radical chemistry, involving multiple viologens, and how it has been exploited in more recent times to template the formation of foldamers and mechanical bonds in both rotaxanes and catenanes leading, in some instances, to the formation of persistent organic radicals in mechanically interlocked molecules (MIMs) and (2) artificial molecular pumps based on flashing ratchet mechanisms that rely on the formation of radical and mixed valence dimers in a reducing medium and subsequently Coulombic repulsions on oxidation in order to perform work away-from-equilibrium on their environments. My lecture will conclude with (a) a discussion of how stereochemistry controls hydrogel formation, (b) a description of how a lock-and-key fit provides a new way to isolate gold and (c) how covalent capture leads to the development of a supramolecular encryption procedure and the formation of 2D-supramolecular polymer films.
“Mechanostereochemistry,” Pure Appl. Chem. 2010, 82, 1569–1574.
“From supramolecular to systems chemistry: Complexity emerging out of simplicity,” Angew. Chem. Int. Ed. 2012, 51, 12902–12903.
“Putting mechanically interlocked molecules (MIMs) to work in tomorrow’s world,” Angew. Chem. Int. Ed. 2014, 53, 11102–11104.
“Radically enhanced molecular recognition,” Nature Chem. 2010, 2, 42–49.
“Folding of oligoviologens induced by radical-radical interactions,” J. Am. Chem. Soc. 2015, 137, 876–885.
“Mechanical bond formation by radical templation,” Angew. Chem. Int. Ed. 2010, 49, 8260–8265.
“A radically configurable six-state compound,” Science 2013, 339, 429–433.
“Great expectations: Can artificial molecular machines deliver on their promise?” Chem. Soc. Rev. 2012, 41, 19–30.
“Relative unidirectional translation in an artificial molecular assembly fueled by light,” J. Am. Chem. Soc. 2013, 135, 18609–18620.
“An artificial molecular pump,” Nature Nanotech. 2015, 10, 547–553.
“Assembly of supramolecular nanotubes from molecular triangles and 1,2-dihalohydrocarbons,” J. Am. Chem. Soc. 2014, 136, 16651–16660.
“A rigid naphthalenediimide triangle for organic rechargeable lithium-ion batteries,” Adv. Mater. 2015, 27, 2907–2912.
“Selective isolation of gold facilitated by second-sphere coordination by α-cyclodextrin,” Nat. Commun. 2013, 4, Article 1855.
“Quantitative emergence of heterorotaxanes by template-directed click chemistry,” Angew. Chem. Int. Ed. 2013, 52, 381–387.
“Tunable solid-state fluorescent materials for supramolecular encryption,” Nat. Commun. 2015, 6, Art
On: November 20, 2015 From: 16h00 To: 17h00View talk
Speaker: Dave Smith (York)
Soft matter systems, self-assembled from molecular-scale building blocks, offer a powerful strategy by which we can program and control the nanoworld, from the molecular-level up. This lecture will explore the ways in which supramolecular chemistry can be used to direct the formation of nanostructures with potential uses as materials and medicines.
We will discuss the self-assembly of soft gel-phase nanomaterials, and in particular, will explore how molecular structure can be translated into nanoscale architectures through non-covalent interactions.1 Directed self-assembly can occur within complex mixtures in order to yield multi-component materials with multiple functions.2 This approach generates soft materials with potential applications ranging from pharmaceutical formulation and pollution control to nanoscale electronics and tissue engineering.3We will also consider how self-assembled systems can interface with biological targets via the formation of multivalent arrays of interactions.4 Such systems can exhibit high affinity binding, with surprising levels of control and selectivity.5 We will demonstrate how this approach can target goals as diverse as gene delivery and coagulation control during major surgery.6
References. 1 (a) W. Edwards, D.K. Smith, J. Am. Chem. Soc. 2013, 135, 5911. (b) W. Edwards, D.K. Smith, J. Am. Chem. Soc. 2014, 136, 1116-1124. 2 (a) D.J. Cornwell, B.O. Okesola, D.K. Smith, Angew. Chem. Int. Ed. 2014, 53, 12461. (b) D.J. Cornwell, D.K. Smith, Mater. Horiz. 2015, 2, 279. 3. (a) A.R. Hirst, B. Escuder, J.F. Miravet, D.K. Smith, Angew. Chem. Int. Ed. 2008, 47, 8002. (b) E.J. Howe, B.O. Okesola, D.K. Smith, Chem. Commun. 2013, 51, 7451. (c) B.O. Okesola, S.K. Suravaram, A. Parkin, D.K. Smith, Angew. Chem. Int. Ed. 2015, in press. 4. A. Barnard, D. K. Smith, Angew. Chem. Int. Ed. 2012, 51, 6572. 5. S.M. Bromfield, D.K. Smith, J. Am. Chem. Soc. 2015, 137, 10056. 6. (a) A. Barnard, P. Posocco, S. Pricl, M. Calderon, R. Haag, M.E. Hwang, V.W.T. Shum, D.W. Pack, D.K. Smith, J. Am. Chem. Soc. 2011, 133, 20288. (b) S.M. Bromfield, P. Posocco, C.W. Chan, M. Calderon, S. E. Guimond, J.E. Turnbull, S. Pricl, D.K. Smith, Chem. Sci. 2014, 5, 1484.
On: December 9, 2015 From: 15h30 To: 16h30View talk