Final Report Summary - SMOLDIF (Small-Molecule Probes of Neuronal Differentiation) The Career Integration Grant (CIG) has enabled transition of Dr. Jakub Švenda from the Max Planck Institute of Molecular Physiology in Germany to the Masaryk University in the Czech Republic. Since 2012, he is an Assistant Professor at the Department of Chemistry at Masaryk University. Since 2015, he is also a research scientist at the International Clinical Research Center, St. Anne’s Hospital in the Czech Republic. Dr. Švenda has established an independent research group in the area of organic synthesis. At present, the laboratory features modern equipment for experimental chemistry research and provides training at the postdoctoral, doctoral and undergraduate level. Over the course of 4 years, the laboratory hosted 1 postdoctoral researcher, 2 PhD students, and 10 undergraduates. Talented students working in the laboratory take part in conferences and research stays abroad (research universities/institutions & pharma companies).Dr. Švenda’s research program is focused on the synthesis of structurally non-trivial natural products with biomedically important activities and on the development of synthetic methodologies. Selected research accomplishments are briefly summarized herein. (A) Dr. Švenda’s laboratory developed a concise, enantioselective, and highly modular synthetic platform for the preparation of an underexplored spirocyclic pharmacophore found in the pseurotin natural product family. Using the developed technology, it was possible to assemble a library of novel spirocycles and submit these to a spectrum of biological screenings (in collaboration). These included assays on neuronal cell differentiation, B-cell immunoglobulin E production, inhibition of human kinases, and modulation of Hedgehog and Wnt signaling. The ongoing chemistry-biology studies will allow for a systematic exploration of the biomedical potential of this class of molecules, which is currently lacking. Novel chemotypes with annotated biology are highly relevant to both basic research and drug discovery. Part of this work was recently submitted for publication in a peer-reviewed scientific journal (B) Identification and optimization of efficient catalytic methodology for the construction of challenging quaternary stereocenters found in many bioactive natural products. The formulated catalytic method appears relatively broad in scope and should find applications in the asymmetric synthesis of chiral molecules well beyond this project. (C) The Marie Curie grant also enabled our laboratory to carry out preliminary experiments on a project targeting efficient synthesis of a structurally complex class of bioactive natural diterpenes. This effort was critical for the subsequent successful application in a competitive funding scheme (junior research grant, Czech Grant Agency). This work will be highly relevant to the biomedical research on key cell-signaling pathways and on underexplored enzymes as therapeutic targets (e.g. adenylyl cyclases). The above research developments have enabled Dr. Švenda to establish several scientific collaborations, both within the Czech Republic and abroad. His laboratory works closely with the medicinal chemistry group of Dr. Kamil Paruch (a former Marie Curie fellow) located at the same department (see: http://orgsyn.sci.muni.cz). Dr. Švenda has scientific interactions with biology groups within the Czech Republic (Masaryk University, Academy of Sciences) and also abroad (Max Planck Institute). Recently, the laboratory participated in a pilot collaboration with the pharmaceutical sector in order to help advance projects requiring non-trivial synthetic chemistry know-how.Aside from the above research activities, Dr. Švenda became extensively involved in teaching at the Masaryk University. He took over a core organic chemistry course (>150 undergraduate students/year) and additionally created a graduate-level class on organic synthesis. Dr. Švenda is in charge of weekly Departmental seminars and delivers popularization chemistry lectures to high-school students on a yearly basis. Funding provided by the Marie Curie Actions grant played a key (decisive) role in the ability of Dr. Švenda to start and maintain an independent research laboratory at the Masaryk University. Flexibility of the grant was immensely important in this process and enabled the most effective support of the non-trivial experimental research, along with the opportunity to compete for additional grant support.
