@article{HuangSchrammHeilmannetal.2016, author = {Huang, Guozheng and Schramm, Simon and Heilmann, J{\"o}rg and Biedermann, David and Kren, Vladim{\´i}r and Decker, Michael}, title = {Unconventional application of the Mitsunobu reaction: Selective flavonolignan dehydration yielding hydnocarpins}, series = {Beilstein Journal of Organic Chemistry}, volume = {12}, journal = {Beilstein Journal of Organic Chemistry}, doi = {10.3762/bjoc.12.66}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-160986}, pages = {662-669}, year = {2016}, abstract = {Various Mitsunobu conditions were investigated for a series of flavonolignans (silybin A, silybin B, isosilybin A, and silychristin A) to achieve either selective esterification in position C-23 or dehydration in a one-pot reaction yielding the biologically important enantiomers of hydnocarpin D, hydnocarpin and isohydnocarpin, respectively. This represents the only one-pot semi-synthetic method to access these flavonolignans in high yields.}, language = {en} } @article{WandreyWurzelHoffmannetal.2016, author = {Wandrey, Georg and Wurzel, Joel and Hoffmann, Kyra and Ladner, Tobias and B{\"u}chs, Jochen and Meinel, Lorenz and L{\"u}hmann, Tessa}, title = {Probing unnatural amino acid integration into enhanced green fluorescent protein by genetic code expansion with a high-throughput screening platform}, series = {Journal of Biological Engineering}, volume = {10}, journal = {Journal of Biological Engineering}, number = {11}, doi = {10.1186/s13036-016-0031-6}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-166304}, year = {2016}, abstract = {Background Genetic code expansion has developed into an elegant tool to incorporate unnatural amino acids (uAA) at predefined sites in the protein backbone in response to an amber codon. However, recombinant production and yield of uAA comprising proteins are challenged due to the additional translation machinery required for uAA incorporation. Results We developed a microtiter plate-based high-throughput monitoring system (HTMS) to study and optimize uAA integration in the model protein enhanced green fluorescence protein (eGFP). Two uAA, propargyl-L-lysine (Plk) and (S)-2-amino-6-((2-azidoethoxy) carbonylamino) hexanoic acid (Alk), were incorporated at the same site into eGFP co-expressing the native PylRS/tRNAPyl CUA pair originating from Methanosarcina barkeri in E. coli. The site-specific uAA functionalization was confirmed by LC-MS/MS analysis. uAA-eGFP production and biomass growth in parallelized E. coli cultivations was correlated to (i) uAA concentration and the (ii) time of uAA addition to the expression medium as well as to induction parameters including the (iii) time and (iv) amount of IPTG supplementation. The online measurements of the HTMS were consolidated by end point-detection using standard enzyme-linked immunosorbent procedures. Conclusion The developed HTMS is powerful tool for parallelized and rapid screening. In light of uAA integration, future applications may include parallelized screening of different PylRS/tRNAPyl CUA pairs as well as further optimization of culture conditions.}, language = {en} } @article{SawatzkyDrakopoulosRoelzetal.2016, author = {Sawatzky, Edgar and Drakopoulos, Antonios and R{\"o}lz, Martin and Sotriffer, Christoph and Engels, Bernd and Decker, Michael}, title = {Experimental and theoretical investigations into the stability of cyclic aminals}, series = {Beilstein Journal of Organic Chemistry}, volume = {12}, journal = {Beilstein Journal of Organic Chemistry}, doi = {10.3762/bjoc.12.221}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-160976}, pages = {2280-2292}, year = {2016}, abstract = {Background: Cyclic aminals are core features of natural products, drug molecules and important synthetic intermediates. Despite their relevance, systematic investigations into their stability towards hydrolysis depending on the pH value are lacking. Results: A set of cyclic aminals was synthesized and their stability quantified by kinetic measurements. Steric and electronic effects were investigated by choosing appropriate groups. Both molecular mechanics (MM) and density functional theory (DFT) based studies were applied to support and explain the results obtained. Rapid decomposition is observed in acidic aqueous media for all cyclic aminals which occurs as a reversible reaction. Electronic effects do not seem relevant with regard to stability, but the magnitude of the conformational energy of the ring system and pK a values of the N-3 nitrogen atom. Conclusion: Cyclic aminals are stable compounds when not exposed to acidic media and their stability is mainly dependent on the conformational energy of the ring system. Therefore, for the preparation and work-up of these valuable synthetic intermediates and natural products, appropriate conditions have to be chosen and for application as drug molecules their sensitivity towards hydrolysis has to be taken into account.}, language = {en} } @article{DaryaeeChangSchiebeletal.2016, author = {Daryaee, Fereidoon and Chang, Andrew and Schiebel, Johannes and Lu, Yang and Zhang, Zhuo and Kapilashrami, Kanishk and Walker, Stephen G. and Kisker, Caroline and Sotriffer, Christoph A. and Fisher, Stewart L. and Tonge, Peter J.}, title = {Correlating drug-target kinetics and in vivo pharmacodynamics: long residence time inhibitors of the FabI enoyl-ACP reductase}, series = {Chemical Science}, volume = {7}, journal = {Chemical Science}, number = {9}, doi = {10.1039/c6sc01000h}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-191218}, pages = {5945-5954}, year = {2016}, abstract = {Drug-target kinetics enable time-dependent changes in target engagement to be quantified as a function of drug concentration. When coupled to drug pharmacokinetics (PK), drug-target kinetics can thus be used to predict in vivo pharmacodynamics (PD). Previously we described a mechanistic PK/PD model that successfully predicted the antibacterial activity of an LpxC inhibitor in a model of Pseudomonas aeruginosa infection. In the present work we demonstrate that the same approach can be used to predict the in vivo activity of an enoyl-ACP reductase (FabI) inhibitor in a model of methicillin-resistant Staphylococcus aureus (MRSA) infection. This is significant because the LpxC inhibitors are cidal, whereas the FabI inhibitors are static. In addition P. aeruginosa is a Gram-negative organism whereas MRSA is Gram-positive. Thus this study supports the general applicability of our modeling approach across antibacterial space.}, language = {en} }