Synthesis of Tool Compounds for Chemical Biology

The study of the mechanism of specific enzymes and the function of these proteins in their cellular environment depends on molecular probes. Herein, we are active in different fields, e.g. the structure-based design of small-molecule inhibitors or the modification of tool compounds for chemical proteomics applications and activity-based protein profiling.

Show Case: Small-molecule inhibitors of Adipose Triglyceride Lipase

Adipose Triglyceride Lipase (ATGL) is the first and rate-limiting enzyme in the catalytic cascade of lipolysis, the mobilization of triglycerides, predominantly from their stores in adipose tissue. Imbalanced lipolysis is highly associated with metabolic disorders like obesity, type-II diabetes and non-alcoholic fatty liver disease (NAFLD). Our efforts in the search for a pharmacological inhibitor of ATGL has led to the discovery Atglistatin®, a specific inhibitor of murine ATGL inhibitor, In vivo studies with Atglistatin® validated ATGL as a potential target in the treatment of aforementioned diseases. We continue working on the improvement of this tool compound in terms of pharmacological properties and species-specificity.

„Development of small molecule inhibitors for adipose triglyceride lipase” N. Mayer, M. Schweiger, M. Romauch, G. F. Grabner, T. O. Eichmann, E. Fuchs, J. Ivkovic, C. Heier, I. Mrak, A. Lass, G. Höfler, C. Fledelius, R. Zechner, R. Zimmermann*, R. Breinbauer*, Nat. Chem. Biol. 2013, 9, 785-787. DOI: 10.1038/nchembio.1359

“Pharmacological inhibition of adipose triglyceride lipase corrects high-fat diet-induced insulin resistance and hepatosteatosis in mice” M. Schweiger*, M. Romauch, R. Schreiber, G. F. Grabner, S. Hütter, P. Kotzbeck, P. Benedikt, T. O. Eichmann, S. Yamada, O. Knittelfelder, C. Diwoky, C. Doler, N. Mayer, W. De Cecco, R. Breinbauer, R. Zimmermann*, R. Zechner*, Nature Commun. 2017, 8, 14859. DOI: 10.1038/ncomms14859

Show Case: Synthesis of alpha-Helix Mimetics as Inhibitors of PPI

Synergistic cooperations between different proteins – protein-protein interactions (PPI) – play a role in all major biological pathways in the body. The number of PPIs in humans is estimated to be at least 50,000, most of which are only poorly characterized. Importantly, misfunction or mutation of certain PPI is connected to various diseases, including several types of cancer. Therefore, developing inhibitors to selectively control disease-associated PPIs is of high interest in drug design.

In our research, we seek to design and synthesize small-molecule inhibitors for PPI based on the concept of mimicking the alpha-helix motif in proteins with an appropriate chemical scaffolds, oligorarenes, which are decorated with the desired amino acid side chains to enable interaction. We have developed a highly efficient and modular strategy to assemble our target compounds from a library of building blocks and are currently investigating their activity against specific cancer cells and other disease states.

“A Modular Synthesis of Teraryl-based alpha-Helix Mimetics, Part 1: Synthesis of Core Fragments with two Electronically Differentiated Leaving Groups” M. Peters, M. Trobe, H. Tan, R. Kleineweischede, R. Breinbauer*, Chem. Eur. J. 2013, 19, 2442-2449. DOI: 10.1002/chem.201203005

“A Modular Synthesis of Teraryl-based alpha-Helix Mimetics, Part 2: Synthesis of 5-Pyridine Boronic Acid Pinacol Ester Building Blocks with Amino Acid Side Chains in 3-Position“ M. Peters, M. Trobe, R. Breinbauer*, Chem. Eur. J. 2013, 19, 2450-2456. DOI: 10.1002/chem.201203006

“Synthesis of a Bcl9 Alpha-Helix Mimetic for Inhibition of PPIs by a Combination of Electrooxidative Phenol Coupling and Pd-Catalyzed Cross Coupling” M. Vareka, B. Dahms, M. Lang, M. H. Hoang, M. Trobe, H. Weber, M. M. Hielscher,  S. R. Waldvogel*, R. Breinbauer*, Catalysts 2020, 10, 340. doi:10.3390/catal10030340

A major goal of our research group is adding new and efficient synthetic methods to the toolbox of Organic Chemistry. In particular, we are interested in developing catalytic methods using transition metal complexes (homogenous catalysis) and enzyms (biocatalysis), or using electrochemical methods (electroorganic synthesis).

Show Case: Posttranslational modifications of proteins via Pd-catalyzed allylation

In the cellular environment many nascent or folded proteins undergo post-translational modifications (PTMs). An especially noteworthy PTM is protein S-prenylation, which plays an important role in controlling protein function and localization. Our lab is interested in the development of new bioconjugation strategies based on Pd-catalyzed allylations, enabling the cysteine-selective prenylation (farnesylation, geranylgeranylation) of unprotected peptides and proteins via a native thioether linkage. Moreover, we are focused on the stapling or cyclization of cysteine-containing peptides.

“Labeling and Natural Post-Translational Modification of Peptides and Proteins via Chemoselective Pd-Catalyzed Prenylation of Cysteine” T. Schlatzer, J. Kriegesmann, H. Schröder, M. Trobe, C. Lembacher-Fadum, S. Santner, A. V. Kravchuk, C, F. W. Becker,* R. Breinbauer*, J. Am Chem. Soc. 2019, 141, 14931-14937.  doi.org/10.1021/jacs.9b08279

“Pd/BIPHEPHOS is an Efficient Catalyst for the Pd-Catalyzed S-Allylation of Thios with High n-Selectivity” T. Schlatzer, H. Schröder, M. Trobe, C. Lembacher-Fadum, S. Stangl, C. Schlögl, H. Weber, R. Breinbauer*, Adv. Synth. Catal. 2020, 362, 331-336. doi.org/10.1002/adsc.201901250

Show Case: Ene-reductase mediated reductive cyclizations

This project is concerned with the biocatalytic synthesis of small cyclic carbaldehydes in a stereoselective way. As biocatalysts different ene-reductases are employed. These enzymes are engineered so they preferentially catalyze a reductive cyclization sequence. Halogenated enals can be used as substrates in this biocatalytic transformation giving the corresponding carbocycles. It is desired do develop ene-reductase variants that are capable of forming cyclic carbaldehydes of different ring sizes in a stereoselective way. Such a biocatalytic system would be a sustainable alternative to classical chemical methods in the synthesis of small carbocycles.

“Asymmetric Reductive Carbocyclization Using Engineered Ene Reductases” K. Heckenbichler, A. Schweiger, L. A. Brandner, A. Binter, M. Toplak, P. Macheroux, K. Gruber, R. Breinbauer*, Angew. Chem. 2018, 130, 7360-7364; Angew. Chem. Int. Ed. 2018, 57, 7240 –7244. doi: 10.1002/anie.201802962