Rings, radicals, and regeneration: the early years of a bioorganic laboratory

This Perspective provides an overview of the progress in two of the original programs in my research group focused on the biosynthesis of the antibiotics nisin, lacticin 481, fosfomycin, and bialaphos. The path from start-up funds to tenure and beyond offers insights into the opportunities realized and missed along the road.     

Tetraphenol-based diphosphite ligands: synthesis, characterization, and application in the rhodium-catalyzed hydroformylation of octenes

A new class of diphosphites is described, based on a tetraphenol backbone. Ligands TP1-TP5 were synthesized and fully characterized and their application in the hydroformylation of octenes was investigated. Ligand TP3, bearing a 1-naphthoxy substituent on the phosphorus, shows the highest regioselectivity toward the linear aldehyde.     

Magnetically Assembled Multisegmented Nanowires and Their Applications

Here we report a cost effective and versatile way of synthesizing and assembling multi‐functional (e.g., gold‐polypyrrole‐nickel‐gold) nanowires. Multisegmented nanowires were synthesized using electrodeposition method for precise control over segment dimensions for proper expression of material functionality. The nanowires were integrated on microfabricated electrodes using magnetic dipole interactions between the ferromagnetic segment in the nanowire and the ferromagnetic electrodes. The electrical properties of multisegmented nanowires showed semiconducting behavior with the activation energy of ca. 0.27 eV for the conducting polymer segment of the nanowire. These nanowire devices showed response towards light and exposure to ammonia, demonstrating their potential use as photonic device and gas sensor, respectively.     

Enhanced charge transfer in a monolayer of the organic charge transfer complex TTF-TNAP on Au(111)

Electronic doping is a key concept for tuning the properties of organic materials. In bulk structures, the charge transfer between donor and acceptor is mainly given by the respective ionization potential and electron affinity. In contrast, monolayers of charge transfer complexes in contact with a metal are affected by an intriguing interplay of hybridization and screening at the metallic interface, determining the resulting charge state. Using scanning tunneling microscopy and spectroscopy, we characterize the electronic properties of the organic acceptor molecule 11,11,12,12-tetracyanonaptho-2,6-quinodimethane (TNAP) adsorbed on a Au(111) surface. The ordered islands remain in a weakly physisorbed state with no charge transfer interaction with the substrate. When the electron donor tetrathiafulvalene (TTF) is added, ordered arrays of alternating TNAP and TTF rows are assembled. In these structures, we find the lowest unoccupied molecular orbital (LUMO) of the free TNAP molecule shifted well below the Fermi level of the substrate. The TNAP is thus charged with more than one electron.     

Investigation of an Allosteric Deoxyhypusine Synthase Inhibitor in P. falciparum

The treatment of a variety of protozoal infections, in particular those causing disabling human diseases, is still hampered by a lack of drugs or increasing resistance to registered drugs. However, in recent years, remarkable progress has been achieved to combat neglected tropical diseases by sequencing the parasites’ genomes or the validation of new targets in the parasites by novel genetic manipulation techniques, leading to loss of function. The novel amino acid hypusine is a posttranslational modification (PTM) that occurs in eukaryotic initiation factor 5A (EIF5A) at a specific lysine residue. This modification occurs by two steps catalyzed by deoxyhypusine synthase (dhs) and deoxyhypusine hydroxylase (DOHH) enzymes. dhs from Plasmodium has been validated as a druggable target by small molecules and reverse genetics. Recently, the synthesis of a series of human dhs inhibitors led to 6-bromo-N-(1H-indol-4yl)-1-benzothiophene-2-carboxamide, a potent allosteric inhibitor with an IC₅₀ value of 0.062 µM. We investigated this allosteric dhs inhibitor in Plasmodium. In vitro P. falciparum growth assays showed weak inhibition activity, with IC₅₀ values of 46.1 µM for the Dd2 strain and 51.5 µM for the 3D7 strain, respectively. The antimalarial activity could not be attributed to the targeting of the Pfdhs gene, as shown by chemogenomic profiling with transgenically modified P. falciparum lines. Moreover, in dose-dependent enzymatic assays with purified recombinant P. falciparum dhs protein, only 45% inhibition was observed at an inhibitor dose of 0.4 µM. These data are in agreement with a homology-modeled Pfdhs, suggesting significant structural differences in the allosteric site between the human and parasite enzymes. Virtual screening of the allosteric database identified candidate ligand binding to novel binding pockets identified in P. falciparum dhs, which might foster the development of parasite-specific inhibitors.     

Further Improvements in High Gain Observer Design for Systems with Structured Nonlinearities

Due to their simple implementation based on a constant gain matrix, high gain observers are very common in practical applications. We consider systems whose dynamics can be decomposed into a linear and a nonlinear part, where the nonlinear part meets some Lipschitz condition. In many cases there exists a finite bound on the maximum feasible Lipschitz constant for which the error dynamics can be stabilized. Necessary and in some sense sufficient conditions for this maximum Lipschitz constant are given in [1]. These results has been improved in [2,3] by taking the structure of the linear part into account. Having a system with one single nonlinearity, the results given in [2,3] are strict. If multiple nonlinearities occur, even this approach tends to be to conservative. In this case, one could additionally take the internal structure of the nonlinearities into account which leads to a larger set of systems for which convergence of the observer error can be guaranteed. Our new approach is based on an approximation of the structured singular value [4] which yields existence conditions in terms of linear matrix inequalities (LMIs). These LMIs may as well be used for the numerical computation of the observer gain. We demonstrate the advantage of our method on an example. (© 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim)     

Influence of F-Anions on the Habit and Growth Mechanism of Potassium-rich Feldspars

Orthoclase-rich alkalic feldspar crystals were grown from melts next to Orthoclase-Albite-Quartz eutectic composition at 2 kb in the presence of a surplus of a supercritical aqueous phase by isobaric cooling at a rate of approximately 10 °C/day. Some runs were made with KF-bearing fluid phase, in two runs the melt was formed during intensive thermoconvection of the fluid phase. Tabular crystals were only formed from F-bearing melts, crystals grown from F-free melt were always fan-shaped. We assume this fact is due to a more easy supply of Al to the growing crystal in melts with F content.