chemical biology; neurite outgrowth; organic sythesis; natural products; molecular design
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.
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.
Kerschgens Isabel P., Gademann Karl (2018), Antibiotic Algae by Chemical Surface Engineering, in ChemBioChem
, 19(5), 439-443.
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.
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
Liffert Raphael, Gademann Karl (2017), Mapping Out Biogenetic Hypotheses by Chemical Synthesis, in CHIMIA International Journal for Chemistry
, 71(12), 841-844.
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.
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.
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.
Gademann Karl (2015), Copy, Edit, and Paste: Natural Product Approaches to Biomaterials and Neuroengineering, in Accounts of Chemical Research
, 48(3), 731-739.
Gademann Karl, Kerschgens Isabel (2015), Direct Preparation of Pyrrolizidines Using Imines and Isonitriles, in Synthesis
, 47(20), 3153-3160.
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.
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.