Ulrich Koert

Publications (66)438.23 Total impact

• Article: Ion-Channels: Goals for Function-Oriented Synthesis.

  Philipp Reiß, Ulrich Koert
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  ABSTRACT: Ion channels provide a conductance pathway for the passive transport of ions across membranes. These functional molecules perform key tasks in biological systems such as neuronal signaling, muscular control, and sensing. Recently, function-oriented synthesis researchers began to focus on ion channels with the goal of modifying the function of existing ion channels (ion selectivity, gating) or creating new channels with novel functions. Both approaches, ion channel engineering and de novo design, have involved synthetic chemists, biochemists, structural biologists, and neurochemists. Researchers characterize the function of ion channels by measuring their conductance in samples of biological membranes (patch clamp) or artificial membranes (planar lipid bilayers). At the single molecule level, these measurements require special attention to the purity of the sample, a challenge that synthetic chemists should be aware of. Ideally, researchers study the function of channels while also acquiring structural data (X-ray, NMR) to understand and predict how synthetic modifications alter channel function. Long-term oriented researchers would like to apply synthetic ion channels to single molecule sensing and to implantat these synthetic systems in living organisms as tools or for the treatment of channelopathies. In this Account, we discuss our own work on synthetic ion channels and explain the shift of our research focus from a de novo design of oligo-THFs and oligo-THF-amino acids to ion channel engineering. We introduce details about two biological lead structures for ion channel engineering: the gramicidin β(6,3) helix as an example of a channel with a narrow ion conductance pathway and the outer membrane porins (OmpF, OmpG) with their open β-barrel structure. The increase and the reversal of ion selectivity of these systems and the hydrophobic match/mismatch of the channel with the phospholipid bilayer are of particular interest. For engineering ion channels, we need to supplement the single-point attachment of a synthetic modulator with the synthesis of a more challenging two-point attachment. The successful function-oriented synthesis of ion channels will require interdisciplinary efforts that include new electrophysiology techniques, efficient synthesis (peptide/protein/organic), and good structural analysis.
  Accounts of Chemical Research 05/2013; · 21.64 Impact Factor
• Source

  Available from: Ruben Bartholomäus

  Article: Total Synthesis of the Postulated Structure of Fulicineroside.

  Ruben Bartholomäus, Fabian Dommershausen, Markus Thiele, Narayan S Karanjule, Klaus Harms, Ulrich Koert
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  ABSTRACT: A total synthesis of the proposed structures of fulicineroside and its aglycone fulicinerine is reported. The tetrasubstituted dibenzofuran substructure was accessible either through a Pd-mediated ortho-metalation or by an Ir-catalyzed meta-borylation. The synthesis of the β,β,α-linked trisaccharide consisting of D-olivose, L-rhodinose, and L-rhamnose was challenged by the unprecedented β-linked rhodinose. A Pd-catalyzed β-selective glycosylation of a 4-epi-rhodinose and a subsequent Mitsunobu inversion provided selectively the β-linked L-rhodinose-L-rhamnose disaccharide. Comparison with the reported data for the natural product and the aglycone suggests a misassignment of the structure of the natural product.
  Chemistry 04/2013; · 5.93 Impact Factor
• Article: Total synthesis of lodopyridone.

  Tobias Burckhardt, Klaus Harms, Ulrich Koert
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  ABSTRACT: A convergent total synthesis of the structurally unprecedented alkaloid lodopyridone was achieved using a cross-coupling of an iodopyridone fragment with a quinolinethiazolylstannane. Key features of the syntheses of the pentasubstituted 4-pyridone were a regioselective bromination of a 4-pyridone derived from kojic acid, a subsequent Cu-mediated introduction of the thioether, and a directed lithiation/iodination step. A chemoselective Negishi cross-coupling of a dibromothiazole and a quinolinylzinc reagent was used to assemble the chloroquinolinethiazol moiety.
  Organic Letters 08/2012; 14(17):4674-7. · 5.86 Impact Factor
• Article: Differentiation of diastereotopic bromine atoms in SN2 reactions of gem-dibromides.

  Niels Münster, Klaus Harms, Ulrich Koert
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  ABSTRACT: A novel directed S(N)2 reaction of conformationally biased gem-dibromides and an arenesulfinate anion is described. The reaction results in the diastereoselective formation of α-bromosulfones. The selectivity originates from pre-coordination of the nucleophile to a free hydroxyl group in the γ-position.
  Chemical Communications 02/2012; 48(13):1866-7. · 6.17 Impact Factor
• Source

  Available from: Wolfgang Grosse

  Article: Flexibility of the N-Terminal mVDAC1 Segment Controls the Channel's Gating Behavior.

  Barbara Mertins, Georgios Psakis, Wolfgang Grosse, Katrin Christiane Back, Anastasia Salisowski, Philipp Reiss, Ulrich Koert, Lars-Oliver Essen
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  ABSTRACT: Since the solution of the molecular structures of members of the voltage dependent anion channels (VDACs), the N-terminal α-helix has been the main focus of attention, since its strategic location, in combination with its putative conformational flexibility, could define or control the channel's gating characteristics. Through engineering of two double-cysteine mVDAC1 variants we achieved fixing of the N-terminal segment at the bottom and midpoint of the pore. Whilst cross-linking at the midpoint resulted in the channel remaining constitutively open, cross-linking at the base resulted in an "asymmetric" gating behavior, with closure only at one electric field´s orientation depending on the channel's orientation in the lipid bilayer. Additionally, and while the native channel adopts several well-defined closed states (S1 and S2), the cross-linked variants showed upon closure a clear preference for the S2 state. With native-channel characteristics restored following reduction of the cysteines, it is evident that the conformational flexibility of the N-terminal segment plays indeed a major part in the control of the channel's gating behavior.
  PLoS ONE 01/2012; 7(10):e47938. · 4.09 Impact Factor
• Article: Quantitative surface-enhanced Raman scattering ultradetection of atomic inorganic ions: the case of chloride.

  Dionysia Tsoutsi, Jose Maria Montenegro, Fabian Dommershausen, Ulrich Koert, Luis M Liz-Marzán, Wolfgang J Parak, Ramon A Alvarez-Puebla
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  ABSTRACT: Surface-enhanced Raman scattering (SERS) spectroscopy can be used for the determination and quantification of biologically representative atomic ions. In this work, the detection and quantification of chloride is demonstrated by monitoring the vibrational changes occurring at a specific interface (a Cl-sensitive dye) supported on a silver-coated silica microbead. The engineered particles play a key role in the detection, as they offer a stable substrate to support the dye, with a dense collection of SERS hot spots. These results open a new avenue toward the generation of microsensors for fast ultradetection and quantification of relevant ions inside living organisms such as cells. Additionally, the use of discrete particles rather than rough films, or other conventional SERS supports, will also enable a safe remote interrogation of highly toxic sources in environmental problems or biological fluids.
  ACS Nano 08/2011; 5(9):7539-46. · 10.77 Impact Factor
• Article: Asymmetric Allylboration of vic-Tricarbonyl Compounds: Total Synthesis of (+)-Awajanomycin.

  Malte Wohlfahrt, Klaus Harms, Ulrich Koert
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  ABSTRACT: To the core: An efficient total synthesis of (+)-awajanomycin was achieved starting with an asymmetric allylboration of a vic-tricarbonyl compound (see scheme; TES=triethylsilyl). A stereoselective alkene dihydroxylation followed by a differentiation of diastereotopic ester groups and a subsequent lactamization gave the bicyclic core structure.
  Angewandte Chemie International Edition 07/2011; 50(36):8404-6. · 13.45 Impact Factor
• Article: Stereo- and regioselective azide/alkyne cycloadditions in carbonic anhydrase II via tethering, monitored by crystallography and mass spectrometry.

  Johannes Schulze Wischeler, Dong Sun, Nicola U Sandner, Uwe Linne, Andreas Heine, Ulrich Koert, Gerhard Klebe
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  ABSTRACT: The carbonic anhydrase II mutant His64Cys was prepared and applied to tethered alkyne/azide cycloaddition reactions. The azide component could be tethered to the enzyme surface through a disulfide bridge, while the alkyne component was reversibly coordinated through a sulfonamide anchor to the zinc ion in the original catalytic center of the enzyme. The incipient orientation of the reactants in the binding site and of the formed triazole product were characterized by crystallography. The reaction progression could be monitored by HPLC-MS analysis.
  Chemistry 05/2011; 17(21):5842-51. · 5.93 Impact Factor
• Article: Strategies and perspectives in ion-channel engineering.

  Wolfgang Grosse, Lars-Oliver Essen, Ulrich Koert
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  ABSTRACT: Membranes form natural barriers that need to be permeable to diverse matter like ions and substrates. This permeability is controlled by ion-channel proteins, which have attracted great interest for pharmaceutical applications. Ion-channel engineering (ICE) modifies biological ion channels by chemical/biological synthetis means. The goal is to obtain ion channels with modified or novel functionality. Three functional strategies exist. The first is the manipulation of the wider pores with robust β-barrel structures, such as those of α-hemolysin and porins. The second engineering approach focuses on the modification of narrow (mostly α-helical) pores to understand selectivity and modes of action. A third functional approach addresses channel gating by (photo)triggering the biological receptor that controls the channel. Several synthetis strategies have been developed and successfully utilized for the synthetic modification of biological ion-channels: the S-alkylation of specifically introduced Cys, protein semisynthesis by native chemical ligation, protein semisynthesis by protein trans-splicing, as well as nonsense-suppression methods. Structural studies (X-ray crystallography, NMR spectroscopy) are necessary to support the functional studies and to afford predictable engineering. The reprogramming and re-engineering of channels can be used for sensing applications, treatment of channelopathies, chemical neurobiology, and providing novel lead compounds for targeting ion channels.
  ChemBioChem 04/2011; 12(6):830-9. · 3.94 Impact Factor
• Article: The imidato-alkenyllithium route for the synthesis of the isoquinocycline-pyrrolopyrrole substructure.

  M André Breuning, Klaus Harms, Ulrich Koert
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  ABSTRACT: A convergent and effective synthesis of the pyrrolopyrrole substructure (CDEFG) of the isoquinocyclines is reported. A key step is a tin-lithium exchange of an imidato-alkenyltin compound (a ring G equivalent) and the subsequent acylation with a lactone. The resulting acetal is used successfully for the ring F closure to the pyrrolopyrrole. The sole formation of the isoquinocycline N,O-acetal epimer is in accordance with the proposed mechanism for the isomerization of quinocyclines to isoquinocyclines.
  Organic Letters 02/2011; 13(6):1402-5. · 5.86 Impact Factor
• Article: Total Syntheses of (+)-Pestaphthalide A and (–)-Pestaphthalide B

  Jonas Schwaben, Jens Cordes, Klaus Harms, Ulrich Koert
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  ABSTRACT: T o t a l S y n t h e s e s o f (+) -P e s t a p h t h a l i d e A a n d (–) -P e s t a p h t h a l i d e Abstract: Total syntheses of (+)-pestaphthalide A and (–)-pestaph-thalide B were achieved. Key steps are an iridium-mediated meta-selective arylborylation, a Suzuki-coupling/Jacobsen-epoxidation sequence, a stereodivergent epoxide opening and an anionic cyclic carbonate/g-lactone rearrangement.
  Synthesis 01/2011; 2011(18):2929. · 2.47 Impact Factor
• Article: Ratiometric optical sensing of chloride ions with organic fluorophore-gold nanoparticle hybrids: a systematic study of design parameters and surface charge effects.

  Andreas Riedinger, Feng Zhang, Fabian Dommershausen, Carlheinz Röcker, Stefan Brandholt, G Ulrich Nienhaus, Ulrich Koert, Wolfgang J Parak
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  ABSTRACT: Colloidal nanoparticles are often stabilized by high surface charges. These create an electrical potential that may strongly affect the concentration of dissolved ions, which presents a formidable problem for the use of nanoparticles in ion-sensing applications. This effect is investigated systematically with organic fluorophore-gold nanoparticle hybrids, which have a chloride-sensitive fluorophore attached at varying distances from their surface. The distance-dependent fluorescence response is quantitatively assessed using fluorescence spectroscopy.
  Small 10/2010; 6(22):2590-7. · 8.35 Impact Factor
• Article: Synthesis of the isoquinocycline-pyrrolopyrrole substructure.

  Jens Cordes, Klaus Harms, Ulrich Koert
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  ABSTRACT: The synthesis of the pyrrolopyrrole substructure of the isoquinocyclines is reported. The pentacyclic (CDEFG) substructure of isoquinocycline A and B, which contains an unusual 2,4,5,6-tetrahydropyrrolo[2,3-b]pyrrole (FG) connected via an N,O-spiro acetal to the anthraquinoid core of the isoquinocycline aglycon has been synthesized. Key steps were a nickel(0)-mediated hydrocyanation of an alkynone, the conversion of an O,O-acetal into an N,O-acetal, and an intramolecular amidine alkylation.
  Organic Letters 09/2010; 12(17):3808-11. · 5.86 Impact Factor
• Article: Good timing in total synthesis: the case of phoslactomycin A.

  Björn Gebhardt, Christian M König, Cornelia Schleth, Mario Dauber, Ulrich Koert
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  ABSTRACT: The importance for the right order of functional group introduction and manipulation (good timing) was demonstrated in the course of a total synthesis of phoslactomycin A. The synthetic strategy comprised a Cu(I)-thiophene carboxylate (CuTC, Liebeskind's reagent)-mediated coupling to introduce the Z,Z-diene at the final stage of the synthesis in the presence of a protected phosphate. Key features for the assembly of the C1-C13 fragment were an asymmetric dihydroxylation, an Evans-aldol reaction and an advanced protective group strategy. The C14-C21 fragment was accessible via an asymmetric 1,2-addition to cyclohexenone and a subsequent diastereoselective ketone reduction. One crucial task was the dihydroxylation of the C8-C9 alkene, the introduction of the C6-C7 double bond and the generation of the C25-nitrogen functionality. A second example consisted of the best sequence for the generation of the functional groups in the core part (first phosphorylation, second iodo-olefination, third azide/carbamate conversion). The synthetic solutions from this approach are compared with the already existing contributions in the phoslactomycin area.
  Chemistry 05/2010; 16(20):5934-41. · 5.93 Impact Factor
• Article: Synthesis, characterization and properties of a new polymerisable surfactant: 12-methacryloyl dodecylphosphocholine.

  Jan Seuring, Philipp Reiss, Ulrich Koert, Seema Agarwal
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  ABSTRACT: A new polymerizable surfactant, 12-methacryloyl dodecylphosphocholine (MDPC), has been synthesized using a three-step procedure in moderate yield. Phase transitions were characterized by DSC and phase behavior in water was determined by surface tension and polarizing microscopy. MDPC showed typical surfactant behavior and self-aggregated to micelles above a distinct concentration. The critical micelle concentration (CMC) of MDPC was determined to be 5 x 10(-4)mol/L. MDPC showed mesomorphic properties between 75 and 86 degrees C as studied by differential scanning calorimetry (DSC). The formation of black lipid membranes was further investigated. The methacrylate functionalized MDPC could form a bilayer membrane (BLM) although it was very unstable (collapsed after 10-30s). However, it was possible to form stable BLMs in mixture with non-polymerizable two chain phospholipids, i.e. asolectin and diphytanoyl phosphatidylcholine (DPhPC). Stable bilayers could be obtained up to a MDPC content of 50 mol%. Gramicidin A was incorporated into MDPC/DPhPC membranes and exhibited ion-channel activity shown by single channel conductivity measurements.
  Chemistry and physics of lipids 03/2010; 163(4-5):367-72. · 2.15 Impact Factor
• Article: Structural and functional characterization of a synthetically modified OmpG.

  Wolfgang Grosse, Philipp Reiss, Simon Reitz, Menekse Cebi, Wolger Lübben, Ulrich Koert, Lars-Oliver Essen
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  ABSTRACT: Chemical modification of ion channels has recently attracted attention due to their potential use in stochastic sensing and neurobiology. Among the available channel templates stable β-barrel proteins have shown their potential for large scale chemical modifications due to their wide pore lumen. Ion-channel hybrids using the outer membrane protein OmpG were generated by S-alkylation with a synthetic modulator and functionally as well as structurally characterized. The dansyl moiety of the used modulator resulted in partial blockage of current though the OmpG channel with its gating characteristics mainly unaffected. The crystal structure of an OmpG-dansyl hybrid at 2.4Å resolution correlates this finding by showing that the modulator lines the inner walling of the OmpG pore. These results underline the suitability of OmpG as a structural base for the construction of stochastic sensors.
  Bioorganic & medicinal chemistry 03/2010; 18(22):7716-23. · 2.82 Impact Factor
• Article: Total synthesis of phoslactomycin A.

  Christian M König, Björn Gebhardt, Cornelia Schleth, Mario Dauber, Ulrich Koert
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  ABSTRACT: A convergent total synthesis of the PP2A-inhibitor phoslactomycin A was achieved using a CuTC-mediated coupling of an alkenyl iodide C1-C13 fragment with an C14-C21 alkenyl stannane in the presence of a protected phosphate. Key features for the assembly of the C1-C13 fragment were an asymmetric dihydroxylation, an Evans-Aldol reaction, and a well-balanced protective group strategy. An asymmetric 1,4-addition to cyclohexenone was the key step in the preparation of the C14-C21 fragment.
  Organic Letters 08/2009; 11(13):2728-31. · 5.86 Impact Factor
• Article: Circular dichroism in ion yields of femtosecond-laser mass spectrometry.

  H Georg Breunig, Gunter Urbasch, Philipp Horsch, Jens Cordes, Ulrich Koert, Karl-Michael Weitzel
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  ABSTRACT: Telling the difference quickly: Femtosecond laser pulses are not only suitable to distinguish structural isomers. They also provide access to the distinction of enantiomers by combination of circular dichroism and mass spectrometry [picture: see text].
  ChemPhysChem 05/2009; 10(8):1199-202. · 3.41 Impact Factor
• Article: Expanding the scope of protein trans-splicing to fragment ligation of an integral membrane protein: towards modulation of porin-based ion channels by chemical modification.

  Steffen Brenzel, Menekse Cebi, Philipp Reiss, Ulrich Koert, Henning D Mootz
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  ABSTRACT: It's raining, it's porin: Fragment ligation of OmpF ion channels was achieved by using the split Psp-GBD Pol intein; this allowed reconstitution of active trimeric porin. In combination with cysteine modification at an internal position, the porin's conductance properties were altered.
  ChemBioChem 04/2009; 10(6):983-6. · 3.94 Impact Factor
• Article: On the function and structure of synthetically modified porins.

  Simon Reitz, Menekse Cebi, Philipp Reiss, Gregor Studnik, Uwe Linne, Ulrich Koert, Lars-Oliver Essen
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  ABSTRACT: The attachment of modulators to a trimeric porin ion channel was investigated (see picture of the trimer with a crown ether modulator (orange)). The interplay of modulator and protein is essential for the conformational heterogeneity of the hybrid channel. Single-site attachment in large pores is not sufficient to change the electrophysiological characteristics of the pores-such change requires additional noncovalent interactions or second-site attachments.
  Angewandte Chemie International Edition 04/2009; 48(26):4853-7. · 13.45 Impact Factor