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Directing Neurite Outgrowth through Synthetic Natural Products

English title Directing Neurite Outgrowth through Synthetic Natural Products
Applicant Gademann Karl
Number 163151
Funding scheme Project funding (Div. I-III)
Research institution Institut für Chemie Universität Zürich
Institution of higher education University of Zurich - ZH
Main discipline Organic Chemistry
Start/End 01.10.2015 - 30.09.2018
Approved amount 565'000.00
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Keywords (5)

chemical biology; neurite outgrowth; organic sythesis; natural products; molecular design

Lay Summary (German)

Lead
Chemische Verbindungen aus der Natur, sogenannte Naturstoffe, sind zentral für das chemische Verständnis der belebten Natur und dienen auch als Inspiration für die Entwicklung von Medikamenten, wie durch den Nobelpreis 2015 für Medizin wieder einmal gezeigt wurde. Dieses Forschungsprojekt beschäftigt sich mit der Herstellung und Untersuchung einer Reihe von Naturstoffen, welche das Wachstum von Neuriten induzieren können. Obwohl schon lange bekannt ist, dass Proteine diese Prozesse starten und steuern können, ist erst seit kurzer Zeit klar, dass auch Naturstoffe diesen grundlegenden Prozess einleiten können. Neuriten sind zentral in der Entwicklung des Gehirns, und somit für Lernen und Gedächtnis, aber auch im Rahmen von neurodegenerativen Krankheiten von grossem Interesse.
Lay summary

Inhalt und Ziel des Forschungsprojekts

Unser Ziel ist es, die Chemie und Biologie von Naturstoffen, welche das Neuritenwachstum induzieren können, zu untersuchen. Dazu verwenden wir verschiedene, interdisziplinäre Forschungsansätze: Die organische Synthese erlaubt den Zugang zu diesen Naturstoffen im chemischen Labor und durch biologische und biochemische Tests können wir die Eigenschaften dieser Moleküle in biologischen Systemen untersuchen. Weiter werden wir vielversprechende chemische Verbindungen auf Oberflächen immobilisieren, um so neuartige Materialien durch Design zu entwerfen und herzustellen, welche das Neuritenwachstum induzieren können.

 Wissenschaftlicher und gesellschaftlicher Kontext des Forschungsprojekts

Naturstoffe sind eine wichtige Inspiration für neuartige Leitstrukturen in der medizinischen Chemie, wie durch viele Nobelpreise gezeigt wurde. Das Verständnis der chemischen und biologischen Eigenschaften von Naturstoffen durch interdisziplinäre Untersuchungen erlaubt es, molekulare Konzepte zu erkennen, welche die im Rahmen der Evolution ausgewählt wurden. Diese Konzepte können dann wiederum in die Entwicklung neuer Leitstrukturen einfliessen, um zum Beispiel im Bereich der neurodegenerativen Krankheiten Erfolge zu erzielen.

 

Direct link to Lay Summary Last update: 09.11.2015

Responsible applicant and co-applicants

Employees

Publications

Publication
Biosynthesis of fragin is controlled by a novel quorum sensing signal
Jenul Christian, Sieber Simon, Daeppen Christophe, Mathew Anugraha, Lardi Martina, Pessi Gabriella, Hoepfner Dominic, Neuburger Markus, Linden Anthony, Gademann Karl, Eberl Leo (2018), Biosynthesis of fragin is controlled by a novel quorum sensing signal, in Nature Communications, 9(1), 1297-1297.
Total Synthesis of the Polyoxygenated Sesquiterpenes Guignarderemophilanes C and D
Ilazi Agron, Liffert Raphael, Gademann Karl (2018), Total Synthesis of the Polyoxygenated Sesquiterpenes Guignarderemophilanes C and D, in Helvetica Chimica Acta, 101(4), e1800011-e1800011.
Antibiotic Algae by Chemical Surface Engineering
Kerschgens Isabel P., Gademann Karl (2018), Antibiotic Algae by Chemical Surface Engineering, in ChemBioChem, 19(5), 439-443.
Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A
Hattori Hiromu, Roesslein Joel, Caspers Patrick, Zerbe Katja, Miyatake-Ondozabal Hideki, Ritz Daniel, Rueedi Georg, Gademann Karl (2018), Total Synthesis and Biological Evaluation of the Glycosylated Macrocyclic Antibiotic Mangrolide A, in Angewandte Chemie International Edition, 57(34), 11020-11024.
Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3)
Hattori Hiromu, Kaufmann Elias, Miyatake-Ondozabal Hideki, Berg Regina, Gademann Karl (2018), Total Synthesis of Tiacumicin A. Total Synthesis, Relay Synthesis, and Degradation Studies of Fidaxomicin (Tiacumicin B, Lipiarmycin A3), in The Journal of Organic Chemistry, 7180-7205.
Mapping Out Biogenetic Hypotheses by Chemical Synthesis
Liffert Raphael, Gademann Karl (2017), Mapping Out Biogenetic Hypotheses by Chemical Synthesis, in CHIMIA International Journal for Chemistry, 71(12), 841-844.
Biological evaluation of pyridone alkaloids on the endocannabinoid system
Chicca Andrea, Berg Regina, Jessen Henning J., Marck Nicolas, Schmid Fabian, Burch Patrick, Gertsch Jürg, Gademann Karl (2017), Biological evaluation of pyridone alkaloids on the endocannabinoid system, in Bioorganic & Medicinal Chemistry, 25(22), 6102-6114.
Total Synthesis of the Sesquiterpenoid Periconianone A Based on a Postulated Biogenesis
Liffert Raphael, Linden Anthony, Gademann Karl (2017), Total Synthesis of the Sesquiterpenoid Periconianone A Based on a Postulated Biogenesis, in Journal of the American Chemical Society, 139(45), 16096-16099.
Formal Total Synthesis of (−)-Jiadifenolide and Synthetic Studies toward seco -Prezizaane-Type Sesquiterpenes
Gomes José, Daeppen Christophe, Liffert Raphael, Roesslein Joel, Kaufmann Elias, Heikinheimo Annakaisa, Neuburger Markus, Gademann Karl (2016), Formal Total Synthesis of (−)-Jiadifenolide and Synthetic Studies toward seco -Prezizaane-Type Sesquiterpenes, in The Journal of Organic Chemistry, 81(22), 11017-11034.
Copy, Edit, and Paste: Natural Product Approaches to Biomaterials and Neuroengineering
Gademann Karl (2015), Copy, Edit, and Paste: Natural Product Approaches to Biomaterials and Neuroengineering, in Accounts of Chemical Research, 48(3), 731-739.
Direct Preparation of Pyrrolizidines Using Imines and Isonitriles
Gademann Karl, Kerschgens Isabel (2015), Direct Preparation of Pyrrolizidines Using Imines and Isonitriles, in Synthesis, 47(20), 3153-3160.
Total Synthesis of the Glycosylated Macrolide Antibiotic Fidaxomicin
Kaufmann Elias, Hattori Hiromu, Miyatake-Ondozabal Hideki, Gademann Karl (2015), Total Synthesis of the Glycosylated Macrolide Antibiotic Fidaxomicin, in Org. Lett., 17(14), 3514-3517.

Collaboration

Group / person Country
Types of collaboration
Prof. Dr. Stephan Sieber, TU München Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
- Exchange of personnel
NCCR Chemical Biology Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Research Infrastructure
Novartis, Dr. Höpfner Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Prof. Peter Scheiffele, Biozentrum Uni Basel Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel
Dr. Zürcher, SuSoS Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
Prof. Dr. Jürg Gertsch, Universität Bern Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Exchange of personnel

Awards

Title Year
CMSZH Travel Award 2018 (Graduate School of Chemical and Molecular Sciences Zurich, May 14, 2018, Switzerland) 2018
Doktorandentag 2017, Universität Zürich, Preis für beste Poster-Präsentation 2017
Swiss Summer School 2017, Trends in Organic Synthesis, Villars-sur-Ollon, Preis für beste Poster-Präsentation 2017
Poster Award, runner’s up, SNF Fall Meeting 2016 2016
Research Poster Award 2016 (Dorothy Crowfoot Hodkin Symposium October 3, 2016, Zurich, Switzerland) 2016

Associated projects

Number Title Start Funding scheme
183310 Ion Mobility Mass Spectrometry to Unscramble Complex Biological Samples 01.09.2019 R'EQUIP
144028 Directing Neurite Outgrowth through Synthetic Natural Products 01.10.2012 Project funding (Div. I-III)

Abstract

Neurite outgrowth constitutes a fundamental process in brain development, and neuritic atrophy is considered a hallmark of many neurodegenerative diseases. While nerve growth factors have been thoroughly investigated in this context, these large proteins display limitations in clinical use. Therefore, small molecules inducing and promoting neuritogenesis could represent an interesting alternative. In this project, we propose to further develop our research program centered around neuritogenic natural products, with the specific aims of (1) obtain small molecule neurotrophins by total synthesis and generating function-optimized derivatives; (2) profile their mechanism of action; and (3) immobilize those compounds on surfaces to generate neuritogenic materials that could facilitate nerve regeneration. In order to address these research questions, we will utilize a multidisciplinary approach involving synthetic organic chemistry, chemical biology, and materials science. Over the last decade, our group has developed excellent competence in these different areas, as evidenced by high-profile publications. Collaborations with leading groups will further leverage our efforts. Concerning the first aim, we plan to develop a general route to the neuritogenic sesquiterpene majucin and its congeners. The proposed route involves key steps such as a radical cyclization, C-H activation and a novel KCN-mediated lactonization approach that should deliver the targets in a relatively short number of synthetic transformations. In a second line of investigation, we target perconianone and congeners by chemical synthesis following a postulated biogenetic route involving a late-stage aldol cyclization to furnish the hitherto unprecedented 6/6/6 carbocyclic sesquiterpene structure. The mechanism of action of these and several other neuritogenic natural products will be investigated in several collaborations using a series of complementary chemical biology approaches, such as HaploInsufficiency Profiling (HIP) and Homozygous deletion Profiling (HOP) assays in yeast, affinity based protein profiling, and endocannabinoid profiling, supported by the design and synthesis of probe compounds. The ultimate aim is to generate neuritogenic surfaces for nerve regeneration based on small molecules. We plan to further develop our recently published catechol systems with regard to (1) profiling newly obtained compounds, (2) additional substrates such as metal oxides and polymeric substrates, and (3) dual mechanism of action systems involving microtubule stabilizing compounds.This project integrates our strong expertise in the synthesis and biological evaluation of natural products, and the design of bioactive materials and leverages these approaches by strong multidisciplinary collaborations to investigate neurite outgrowth, a fundamental process in neuroscience.
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