Robin Panisch

Design, synthesis, and biological testing of novel naphthoquinones as substrate-based inhibitors of the quinol/fumarate reductase from Wolinella succinogenes.

Novel naphthoquinones were designed, synthesized, and tested as substrate-based inhibitors against the membrane-embedded protein quinol/fumarate reductase (QFR) from Wolinella succinogenes, a target closely related to QFRs from the human pathogens Helicobacter pylori and Campylobacter jejuni. For a better understanding of the hitherto structurally unexplored substrate binding pocket, a structure-activity relationship (SAR) study was carried out. Analogues of lawsone (2-hydroxy-1,4-naphthoquinone 3a) were synthesized that vary in length and size of the alkyl side chains (3b-k). A combined study on the prototropic tautomerism of 2-hydroxy-1,4-naphthoquinones series indicated that the 1,4-tautomer is the more stable and biologically relevant isomer and that the presence of the hydroxyl group is crucial for inhibition. Furthermore, 2-bromine-1,4-naphthoquinone (4a-c) and 2-methoxy-1,4-naphthoquinone (5a-b) series were also discovered as novel and potent inhibitors. Compounds 4a and 4b showed IC50 values in low micromolar range in the primary assay and no activity in the counter DT-diaphorase assay.

The correlation of cathodic peak potentials of vitamin K3 derivatives and their calculated electron affinities: The role of hydrogen bonding and conformational changes

2-methyl-1,4-naphtoquinone 1 (vitamin K(3), menadione) derivatives with different substituents at the 3-position were synthesized to tune their electrochemical properties. The thermodynamic midpoint potential (E(1/2)) of the naphthoquinone derivatives yielding a semi radical naphthoquinone anion were measured by cyclic voltammetry in the aprotic solvent dimethoxyethane (DME). Using quantum chemical methods, a clear correlation was found between the thermodynamic midpoint potentials and the calculated electron affinities (E(A)). Comparison of calculated and experimental values allowed delineation of additional factors such as the conformational dependence of quinone substituents and hydrogen bonding which can influence the electron affinities (E(A)) of the quinone. This information can be used as a model to gain insight into enzyme-cofactor interactions, particularly for enzyme quinone binding modes and the electrochemical adjustment of the quinone motif.

Simulation of absorption sites of acetone at ice: (0001) surface, bulk ice and small-angle grain boundaries

Local structures and energies were calculated for the interaction of acetone molecules with ice Ih at the (0001) surface, in the bulk and at small-angle grain boundaries. Force-field methods were used; for the surface additionally ab initio calculations were done. An ordered crystal-structure model of ice Ih in space groupP1121 (Z = 8) was used. The small-angle grain boundary was set up as a series of line defects with Burgers vectors of [2/3 1/3 1/2] (in the hexagonal lattice of ice Ih). All calculations were carried out with one or two acetone molecules in a sufficiently large simulation box containing up to 4608 water molecules, representing the low concentration of acetone in the atmosphere. The adsorption on the surface is energetically preferred. The acetone molecule is bound to the surface by two hydrogen bonds. This result is in contrast to earlier works with high acetone concentrations where only one hydrogen bond is formed. With two hydrogen bonds the adsorption enthalpy is calculated as −41.5 kJ mol−1, which is in agreement with experimental results. The interaction at small-angle grain boundaries is energetically less favourable than at the surface but much more favourable than in the bulk ice. In bulk ice and at small-angle grain boundaries the acetone molecule is bound by two hydrogen bonds like at the surface. The incorporation of acetone in bulk ice distorts the crystal structure significantly, whereas an incorporation at a small-angle grain boundary leads only to a minor distortion.

Cyclic Silylated Onium Ions of Group 15 Elements

Five- and six-membered cyclic silylated onium ions of group 15 elements I were synthesized by intramolecular cyclization of transient silylium ions II. Silylium ions II were prepared by the hydride transfer reaction from silanes III using trityl cation as hydride acceptor. It was found that smaller ring systems could not be obtained by this approach. In these cases tritylphosphonium ions IV were isolated instead. Cations I and IV were isolated in the form of their tetrakispentafluorphenyl borates and characterized by multinuclear NMR spectroscopy and, in two cases, by X-ray diffraction analysis. Cyclic onium ions I showed no reactivity similar to that of isoelectronic intramolecular borane/phosphane frustrated Lewis pairs (FLPs). The results of DFT computations at the M05-2X level suggest that the strength of the newly formed Si-E linkage is the major reason for inertness of I[B(C6F5)4] versus molecular hydrogen.

Investigation on the electrochemistry and cytotoxicity of the natural product marcanine A and its synthetic derivatives

The electrochemistry and cytotoxicity of marcanine A were investigated by electrochemical, computational and cellular studies. To enable a structure–toxicity-relationship of the natural product, eleven novel synthetic derivatives with different electrochemical properties were synthesized and tested. Derivative 5 revealed a GI50 in the low μM range, being more active than the actual natural product. A clear correlation was found between the experimental and the calculated data.