Searching for Selective Reactions on Complex Molecular Scaffolds Scott J. Miller Department of Chemistry, 225 Prospect Street, Yale University, New Haven, Connecticut 06520-8107, USA [email protected]Natural products have provided perennial inspiration for the development of synthetic methods, and enzymes have provided an analogous platform for the conception of new catalysts. This lecture will recount an interplay of experiments stimulated by these two major classes of naturally occurring substances. Specifically, the discovery and use of peptides as catalysts for a variety of asymmetric bond formations will be presented. Likewise, applications of these catalysts to the synthesis and selective modification of complex molecules, including biologically active natural products, will be described. A particular emphasis will be placed on reactions that present unusual stereochemical challenges. An analysis of catalyst types that may be brought to bear on complex molecular environments will also be included.
Transcript
Searching for Selective Reactions on Complex Molecular Scaffolds
Scott J. Miller Department of Chemistry, 225 Prospect Street, Yale University, New Haven,
Natural products have provided perennial inspiration for the development of synthetic methods, and enzymes have provided an analogous platform for the conception of new catalysts. This lecture will recount an interplay of experiments stimulated by these two major classes of naturally occurring substances. Specifically, the discovery and use of peptides as catalysts for a variety of asymmetric bond formations will be presented. Likewise, applications of these catalysts to the synthesis and selective modification of complex molecules, including biologically active natural products, will be described. A particular emphasis will be placed on reactions that present unusual stereochemical challenges. An analysis of catalyst types that may be brought to bear on complex molecular environments will also be included.
Do we Fully Understand what Controls Kinetic Selectivity in Chemistry?
B. K. Carpenter, School of Chemistry, Cardiff University, Cardiff CF10 3AT, UK
Arguably, control of selectivity is the most important topic in synthetic methodology. Usually, the selectivity in question is kinetic rather than thermodynamic, and so the problem appears to be defined by controlling the relative free energies of the transition states for competing reaction pathways. However, in this presentation, the speaker will argue that many reactions exhibit selectivities (product ratios) that cannot be understood in these terms. There are two principal reasons. First, we organic chemists have typically thought of our reactions in terms of energy profiles that are too simplified. They are unable to describe phenomena such as reaction-path bifurcation. When bifurcations occur (which they do frequently and for many different reaction types), there currently exist no simple methods that can predict product ratios. Second, we typically ignore the energy that may be deposited in transient intermediates during their formation. However, it turns out that product ratios from a reactive intermediate can depend not only on how much energy is deposited during its formation, but also on exactly how it is deposited. Efforts to control selectivity by conventional means (catalysis, change of solvent, etc.) when phenomena such as these are occurring will be guaranteed to fail. Examples will be discussed.
Towards spatio-temporally resolved chemistry:
From remote control to surface confinement
S. Hecht
Department of Chemistry, Humboldt-Universität zu Berlin, Germany Email: [email protected] URL: www.hechtlab.de
The foundation of the chemical enterprise has always been the creation of new molecular entities, such as pharmaceuticals or polymeric materials. Over the past decades, this continuing effort of designing compounds with improved properties has been complemented with a strong effort to render their preparation (more) sustainable by implementing atom as well as energy economic strategies. However, besides being concerned with what and how to make, it should become increasingly important for chemists to control when and where chemical reactions take place. The ultimate goal is to perform chemistry with high spatial and temporal resolution, which would allow to time reactions, for example in simple cascades or complex chemical networks, and to localize them, for example in 2D patterns for array chip technologies or even in 3D. We seek to gain control over time and space of a chemical transformation of choice by two approaches: One using a gate, which upon the action of an external stimulus acts as a “remote control”, and another exploiting surface-confined and tip-controlled reactivity. While in the first approach we are developing photoswitchable catalysts as well as tags, in the latter one we have developed an on-surface polymerization route to generate new hybrid materials. An overview over our activities will be presented and our most recent progress in these areas will be described. References Recent review: R. Göstl, A. Senf, and S. Hecht Chem. Soc. Rev. 2014, 43, 1982-1996. Ten most significant original research papers on this topic: R. Göstl and S. Hecht Angew. Chem. Int. Ed. DOI: 10.1002/anie.201310626. S. Castellanos et al. Angew. Chem. Int. Ed. 2013, 52, 13985-13990. Z. Yu and S. Hecht Angew. Chem. Int. Ed. 2013, 52, 13740-13744. C. Bronner et al. Angew. Chem. Int. Ed. 2013, 52, 4422-4425 E. Orgiu et al., Nat. Chem. 2012, 4, 675-679. L. Lafferentz et al. Nat. Chem. 2012, 4, 215-220. R. S. Stoll et al. J. Am. Chem. Soc. 2009, 131, 357-367. L. Lafferentz et al. Science 2009, 323, 1193-1197. C. Dri et al. Nat. Nanotechn. 2008, 3, 649-653. L. Grill et al. Nat. Nanotechn. 2007, 2, 687-691.
Bioinspired Chemistry with Peptides
Helma Wennemers Laboratory of Organic Chemistry, D-CHAB, ETH Zurich, Wolfgang Pauli Strasse 10, CH-8093 Zurich
In nature, proteins fulfill manifold different functions and are crucial as, for example,
enzymes or templates for the controlled formation of structural components such as bones. The
Wennemers group is intrigued by the question whether also peptides with significantly lower
molecular weights compared to proteins can fulfill functions for which nature evolved large
macromolecules. Specifically we ask whether peptides can serve as effective asymmetric
catalysts, templates for the controlled formation of metal nanoparticles, synthetic collagen based
materials, or tumor targeting vectors. The lecture will illustrate recent developments with a focus
on proline-rich peptides.
Selective oxidations using molecular oxygen - the power of biocatalysis
Prof. Sabine L. Flitsch, The University of Manchester, School of Chemistry & MIB, 131 Princess Street, Manchester M1 7DN, United Kingdom Molecular oxygen has many advantages as an oxidant, in particular as far as cost and environmental impact is concerned. In Nature, oxygen is widely used as an oxidant in metabolic and catabolic pathways by enzymes, which can catalyse oxidations under mild reaction conditions with high chemo- regio- and stereoselectivity. These enzymes have attracted interest as biocatalysts for organic synthesis and the talk will present our current work on members of two such enzyme classes, the oxidases and oxygenases. Galactose oxidase from Fusarium sp. is an alcohol oxidase, which catalyses the selective oxidation of the C-6 primary alcohol of the sugar galactose and derivatives to the corresponding aldehydes using molecular oxygen and generating hydrogen peroxide. Using molecular evolution techniques, we have significantly expanded the substrate range of this enzyme to other alcohol sugars and glycoconjugates. [1,2] P450 monoogygenases catalyse a wide range of oxidations such as C-H activation, aromatic hydroxylations, epoxidation, sulfoxidations and oxidative dealkylation reactions. The requirements for complex protein co-factors have held back their broader applications in organic synthesis. This talk will discuss recent results from our group that aim to address these limitations including the use of self-sufficient systems and the integration of P450-catalysed steps in synthetic biology platforms for the production of fine chemicals and pharmaceuticals. [3,4,5,6] Literature: [1] J. Rannes et al, J. Am. Chem. Soc. 2011, 133, 8436. [2] A. Ioannou et al., Chem. Commun.
2011, 47, 11228. [3] F. Sabbadin F, et al. CHEMBIOCHEM. 2010 , 11(7), 987. [4] E. O'Reilly et al,
Chem. Commun. 2011 , 47(9), 2490.[5] E. O’Reilly et al, Beilstein J Org Chem. 2012, 8: 496.-500. [6]
M. Goswami, Ames/USA, A. Cowell, Bloomington/USA, D. Kabotso, Bloomington/USA
Prof. Dr. Nicola Pohl, Indiana University, 212 S. Hawthorne Drive, Bloomington, IN 47405, USA
Significant advances in glycobiology are often stalled by the lack of diverse and chemically well-defined glycan structures. For automation to play as important a role in the synthesis of oligosaccharides as it does currently in peptide and nucleic acid production, the major bottleneck of building block access must be overcome. Here, progress toward addressing this building block issue, in part by the development of simpler thioglycoside activation protocols, will be discussed. Specifically, newly discovered chemistry of bismuth and progress toward understanding the mechanism of this glycosylation chemistry will be explored.
Literature: [1] M. Goswami, A, Ellern, N. L. B. Pohl, Angew. Chem. Int. Ed. 2013, 52, 6983.
DNA Bases Beyond Watson and Crick
T. Carell
Department of Chemistry, LMU Munich, Butenandtstr. 5-13, 81377 Munich/DE
I am going to discuss the latest results about the function and distribution of the new epigenetically relevant nucleobases 5-hydroxymethylcytosine (hmC), 5-formylcytosine (fC), 5-carboxycytosine (caC) and 5-hydroxymethyluracil.[1] These nucleobases seem to play an important role in epigenetic reprogramming of stem cells and some of these molecules are also detected at relatively high levels in brain tissues. I will present new synthetic routes that enable preparation of these compounds and of the corresponding phosphoramidites using modern metal organic chemistry. Finally, the lecture covers new approached that allow us to gain insights into the chemistry and biology of stem cell development processes. In particular mass spectroscopy in combination with the use of stable-isotope labeled material allows investigation of the distribution of these novel bases in various tissues and during stem cell development. The recently discovered base formylcytosine for example, is present at relatively high levels in stem cells and its distribution varies during development in a wave like fashion. I am going to describe the distribution of carboxycytosine in somatic tissues and in stem cells and will provide new quantitative data derived from a detailed mass spectrometric analysis. In order to elucidate the function of the nucleobases we devised a new isotope tracing experiment that enables us to unravel the biochemistry of the bases with high precision and accuracy directly in stem cells. I will discuss the synthesis of double [15N]-labeled hmC, fC and caC and the preparation of DNA containing these isotopologes. The DNA strands are subsequently added to stem cell nuclear extracts and the formation of the novel nucleobases is followed by high sensitive mass spectrometry.[1]
Scheme 1. Depiction of the epigenetic bases hmC, fC, and caC [1] Schiesser, B. et al. Angew. Chem. Int. Ed. 2012, DOI: 10.1002/anie.201202583.
Fluorine’s specialities in peptide and protein environments
Vivian Asante, Shijie Ye, Susanne Huhmann, Allison Berger, Beate Koksch
Institute of Chemistry and Biochemistry, Freie Universität Berlin, Berlin, Germany
[3] Asante, V.; Mortier, J.; Wolber, G.; Koksch, B. submitted.
[4] Ye, S.; Loll, B.; Berger, A.A.; Mülow, U.; Alings, A.; Koksch, B. submitted.
Figure 1:
a) Non-natural
amino acids involved
in our studies,
b) Inhibition of
β-trypsin by BPTI
variants,
c) Lys15TfeGly
occupancy in the S1
binding pocket of
β-trypsin.
Rational Design of Inhibitors of the Coagulation Cascade
H. Priepke, Biberach/D
Dr. Henning Priepke, Boehringer-Ingelheim Pharma GmbH & Co. KG, Birkendorfer Str.
65, 88397 Biberach an der Riss
The unwanted formation of blood clots is the underlying cause of a number of serious diseases like stroke, heart attack or venous thromboembolism which are associated with a high morbidity and mortality rate. While Vitamin K antagonists were commonly used as oral anticoagulants for long term treatment in the past, their unpredictable pharmacokinetic profile and their potential for drug-drug or drug-food interactions is leaving room for medical improvement. Therefore, the pharmaceutical industry devoted tremendous research capacities to the identification of new anticoagulants during the last two decades. Most activities concentrated on the identification of inhibitors of enzymes located in the coagulation cascade, especially the serine proteases thrombin and FXa. [1] Boehringer Ingelheim’s research activities culminated in the identification of the thrombin inhibitor Dabigatran – the first new oral anticoagulant which reached block-buster status. [2] This contribution will summarize our in-house research activities directed towards the identification of FXa inhibitors as clinical candidates. The impact of structure-based drug design on our lead optimization process will be a focus of this presentation. Especially, X-ray analysis of inhibitor-protease cocrystals helped broadening the structural basis of our leads and accelerated the search for potential new anticoagulants. [3] In addition, a number of issues and pitfalls - typical for late stage lead optimization - will be discussed. Literature: [1] A. Straub, S. Roehrig, A. Hillisch, Angew. Chem. Int. Ed. 2011, 50, 4574-4590. [2] J van Ryn, A. Goss, N. Hauel, W. Wienen, H. Priepke, H. Nar, A. Clemens, Front. Pharmacol., doi: 10.3389/fphar.2013.00012. [3] H. Nar, Trends in Pharmacological Sciences 2012, 33, 279-288.
Sugars and Proteins: Towards a Synthetic Biology
B. Davis, Oxford/GB
Professor Ben Davis, University of Oxford, Chemistry Research Laboratory, 12 Mansfield Road, OX1 3TA Oxford
Sugars and Post-Translational Modifications are critical biological markers that modulate the properties of proteins. Our work studies the interplay of proteins, sugars and modifications. Synthetic Biology's development at the start of this century may be compared with Synthetic Organic Chemistry's expansion at the start of the last; after decades of isolation, identification, analysis and functional confirmation the future logical and free-ranging redesign of biomacromolecules offers tantalizing opportunities. This lecture will cover emerging areas in our group in chemical protein construction with an emphasis on new bond-forming processes compatible with biology: (i) New methods are required: despite 80-years-worth of non-specific, chemical modification of proteins, precise methods in protein chemistry remain rare. The development of efficient, complete, chemo- and regio-selective methods, applied in benign aqueous systems to redesign the structure and function of proteins both in vitro and in vivo will be presented. (ii) 'Synthetic Biologics' and their applications: drug delivery; selective protein degradation; nanomolar inhibitors of bacterial interactions; gene delivery vehicles; radio-dose delivery vehicles; probes of in vivo function and non-invasive presymptopmatic disease diagnosis.
Selective payload delivery from nanocapsules
Katharina Landfester
Max-Planck-Institut für Polymerforschung, Ackermannweg 10, Mainz
Polymeric nanocapsules offer the versatility to cover a wide range of mesoscopic properties for sophisticated applications. By means of the miniemulsion process, we can design custom-made nanocapules for different purpose. The accumulation of understanding the formation process has led to successful and precise control of important nanocapsule parameters such as size, shape, morphology, degradation, release kinetics and surface functionalization. This degree of control is unique and allows us to tune specific properties tailored to particular applications. Furthermore, the encapsulation and release of a great variety of payloads, ranging from hydrophobic to hydrophilic substances has been successfully achieved in a highly controlled manner and with an unmatched high encapsulation efficiency. The preparation of nanocontainers with a hydrophilic core from water-in-oil emulsions and their subsequent transfer to aqueous medium is of special importance since it enables the efficient encapsulation of hydrophilic payloads in large quantities. However, major challenges are associated with their synthesis include low colloidal stability, leakage of encapsulated payloads due to osmotic pressure, and a demanding transfer of the nanocontainers from apolar to aqueous media. We present a general approach for the synthesis of polymer nanocontainers that are colloidally stable, not sensitive to osmotic pressure, and responsive to environmental stimuli that trigger release of the nanocontainer contents. Additionally, the nanocontainers can selectively deliver one or two different payloads upon oxidation and changes of pH or temperature. Our approach uniquely enables the synthesis of nanocontainers for applications in which aqueous environments are desired or inevitable.
Semi‐synthesis of proteins to expand biological function
Annette G. Beck‐Sickinger, Bioorganic Chemistry and Biochemistry, Institute of Biochemistry,
University of Leipzig, Brüderstr. 34, 04103 Leipzig, beck‐sickinger@uni‐leipzig.de
Protein ligation allows the introduction of a wide range of
modifications into proteins that are not accessible by
mutagenesis. This includes non proteinogenic amino acids and
even backbone modification. Recent reports on modified
chemokine variants by ligation technologies will be presented and
the development of the first protein with a full secondary
structure motif exchanged by a helix that exclusively consists of β‐
amino acids will be introduced. Furthermore the first protein
activatable by light by rearrangement of
a depsi‐peptide bond is described. Combining different ligation
methods immobilization and specific release of chemokines was
achieved, which is of major importance for the gradient forming
activity of chemokines. Examples are shown for CXCL8 (interleukin
8, IL‐8) and CXCL12 (stromal derived factor 1, SDF 1) including
their chemical and structural characterization as well as the most
frequently used assays.
Literature
Steinhagen M, Hoffmeister PG, Nordsieck K, Hötzel R, Baumann L, Hacker MC, Schulz‐Siegmund M, Beck‐Sickinger AG. Matrix metalloproteinase 9 (MMP‐9) mediated release of MMP‐9 resistant stromal cell‐derived factor 1α (SDF‐1α) from surface modified polymer films. ACS Appl Mater Interfaces. 2014;6(8):5891‐9.
Baumann L, Beck‐Sickinger AG. Photoactivatable chemokines‐‐controlling protein activity by light. Angew Chem Int Ed Engl. 2013;52(36):9550‐3.
Schultz S, Saalbach A, Heiker JT, Meier R, Zellmann T, Simon JC, Beck‐Sickinger AG. Proteolytic activation of prochemerin by kallikrein 7 breaks an ionic linkage and results in C‐terminal rearrangement. Biochem J. 2013;452(2):271‐80. d
Nordsieck K, Pichert A, Samsonov SA, Thomas L, Berger C, Pisabarro MT, Huster D, Beck‐Sickinger AG. Residue 75 of interleukin‐8 is crucial for its interactions with glycosaminoglycans. Chembiochem. 2012;13(17):2558‐66.
Bellmann‐Sickert K, Beck‐Sickinger AG. Palmitoylated SDF1α shows increased resistance against proteolytic degradation in liver homogenates. ChemMedChem. 2011;6(1):193‐200.
David R, Günther R, Baumann L, Lühmann T, Seebach D, Hofmann HJ, Beck‐Sickinger AG. Artificial chemokines: combining chemistry and molecular biology for the elucidation of interleukin‐8 functionality. J Am Chem Soc. 2008;130(46):15311‐7.
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