Efficient Entropy-Driven Inhibition of Dipeptidyl Peptidase III by Hydroxyethylene Transition-State Peptidomimetics

Dipeptidyl peptidase III (DPP3) is a ubiquitously expressed Zn-dependent protease, which plays an important role in regulating endogenous peptide hormones, such as enkephalins or angiotensins. In previous biophysical studies, it could be shown that substrate binding is driven by a large entropic contribution due to the release of water molecules from the closing binding cleft. Here, the design, synthesis and biophysical characterization of peptidomimetic inhibitors is reported, using for the first time an hydroxyethylene transition-state mimetic for a metalloprotease. Efficient routes for the synthesis of both stereoisomers of the pseudopeptide core were developed, which allowed the synthesis of peptidomimetic inhibitors mimicking the VVYPW-motif of tynorphin. The best inhibitors inhibit DPP3 in the low μM range. Biophysical characterization by means of ITC measurement and X-ray crystallography confirm the unusual entropy-driven mode of binding. Stability assays demonstrated the desired stability of these inhibitors, which efficiently inhibited DPP3 in mouse brain homogenate.     

Polyampholytic Graft Copolymers as Matrix for TiO2/Eosin Y/[Mo3S13]2− Hybrid Materials and Light-Driven Catalysis

An effective strategy to enhance the performance of inorganic semiconductors is moving towards organic-inorganic hybrid materials. Here, we report the design of core–shell hybrid materials based on a TiO₂ core functionalized with a polyampholytic (poly(dehydroalanine)-graft-(n-propyl phosphonic acid acrylamide) shell (PDha-g-PAA@TiO₂). The PDha-g-PAA shell facilitates the efficient immobilization of the photosensitizer Eosin Y (EY) and enables electronic interactions between EY and the TiO₂ core. This resulted in high visible-light-driven H₂ generation. The enhanced light-driven catalytic activity is attributed to the unique core–shell design with the graft copolymer acting as bridge and facilitating electron and proton transfer, thereby also preventing the degradation of EY. Further catalytic enhancement of PDha-g-PAA@TiO₂ was possible by introducing [Mo₃S₁₃]²⁻ cluster anions as hydrogen-evolution cocatalyst. This novel design approach is an example for a multi-component system in which reactivity can in future be independently tuned by selection of the desired molecular or polymeric species.     

Zeta-potential measurements of OTS-covered silica samples

We have carried out zeta-potential measurements on two different OTS (octadecyl-trichlorosilane)-covered silicas (fused silica, quartz 0001) prepared under identical conditions. Streaming current measurements on the fused silica supported OTS sample indicate a well reproducible IEP of 3.5. The major part of the study focused on the quartz 0001 supported sample with an IEP lower than that of the fused silica support and in agreement with that found in a spectroscopic study. The IEP in water (on addition of HCl) was found at around pH 3, and appeared to shift to lower values in three subsequent measurements. A final measurement after a separate series in KCl media gave the same IEP as obtained in the very first measurement, suggesting that the experiments did not significantly change the interfacial properties despite a large number of experiments. In one series of measurements care was taken to exclude any cations other than protons from the measurements, such that protons are the only counter-ions to the negative net charge. While our IEPs with the quartz support agree well with recent estimates from sum frequency generation (SFG) investigations, none of the zeta-potential vs pH curves would mimic a pattern experimentally observed in the amplitude of the “ice-like” water band between pH 3.5 and 5 in that SFG study. Furthermore, our results do not indicate any significant chloride-ion adsorption in KCl systems, but instead the shift of the IEP with increasing KCl to higher pH values rather indicates specific effects of potassium ions. Under conditions more relevant to the spectroscopic study (i.e. in absence of potassium) no specific pattern reminiscent of the SFG results was found. When tested it was found that surface conductivity was negligible.     

Structure–Property Relationships in Click‐Derived Donor–Triazole–Acceptor Materials

To shed light on intramolecular charge‐transfer phenomena in 1,2,3‐triazole‐linked materials, a series of 1,2,3‐triazole‐linked push–pull chromophores were prepared and studied experimentally and computationally. Investigated modifications include variation of donor and/or acceptor strength and linker moiety as well as regioisomers. Photophysical characterization of intramolecular charge‐transfer features revealed ambipolar behavior of the triazole linker, depending on the substitution position. Furthermore, non‐centrosymmetric materials were subjected to second‐harmonic generation measurements, which revealed the high nonlinear optical activity of this class of materials.     

Monofluoroalkene-Isostere as a 19F NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane-Bound PGLa and (KIGAKI)3

Solid-state ¹⁹F NMR is a powerful method to study the interactions of biologically active peptides with membranes. So far, in labelled peptides, the ¹⁹F-reporter group has always been installed on the side chain of an amino acid. Given the fact that monofluoroalkenes are non-hydrolyzable peptide bond mimics, we have synthesized a monofluoroalkene-based dipeptide isostere, Val-Ψ[(Z)-CF=CH]-Gly, and inserted it in the sequence of two well-studied antimicrobial peptides: PGLa and (KIGAKI)₃ are representatives of an α-helix and a β-sheet. The conformations and biological activities of these labeled peptides were studied to assess the suitability of monofluoroalkenes for ¹⁹F NMR structure analysis.     

Minimal kernels of Dirac operators along maps

Let M be a closed spin manifold and let N be a closed manifold. For maps and Riemannian metrics g on M and h on N, we consider the Dirac operator of the twisted Dirac bundle . To this Dirac operator one can associate an index in . If M is 2‐dimensional, one gets a lower bound for the dimension of the kernel of out of this index. We investigate the question whether this lower bound is obtained for generic tupels .     

A Thioxanthone Sensitizer with a Chiral Phosphoric Acid Binding Site: Properties and Applications in Visible Light-Mediated Cycloadditions

A chiral phosphoric acid with a 2,2’-binaphthol core was prepared that displays two thioxanthone moieties at the 3,3’-position as light-harvesting antennas. Despite its relatively low triplet energy, the phosphoric acid was found to be an efficient catalyst for the enantioselective intermolecular [2+2] photocycloaddition of β-carboxyl-substituted cyclic enones (e.r. up to 93:7). Binding of the carboxylic acid to the sensitizer is suggested by NMR studies and by DFT calculations to occur by means of two hydrogen bonds. The binding event not only enables an enantioface differentiation but also modulates the triplet energy of the substrates.     

Generalized sensitivity analysis of nonlinear programs using a sequence of quadratic programs

ABSTRACT

Local sensitivity information is obtained for KKT points of parametric NLPs that may exhibit active set changes under parametric perturbations; under appropriate regularity conditions, computationally relevant generalized derivatives of primal and dual variable solutions of parametric NLPs are calculated. Ralph and Dempe obtained directional derivatives of solutions of parametric NLPs exhibiting active set changes from the unique solution of an auxiliary quadratic program. This article uses lexicographic directional derivatives, a newly developed tool in nonsmooth analysis, to generalize the classical NLP sensitivity analysis theory of Ralph and Dempe. By viewing said auxiliary quadratic program as a parametric NLP, the results of Ralph and Dempe are applied to furnish a sequence of coupled QPs, whose unique solutions yield generalized derivative information for the NLP. A practically implementable algorithm is provided. The theory developed here is motivated by widespread applications of nonlinear programming sensitivity analysis, such as in dynamic control and optimization problems.     

Asymmetric Carboxycyanation of Aldehydes by Cooperative AlF/Onium Salt Catalysts: from Cyanoformate to KCN as Cyanide Source

Asymmetric 1,2-additions of cyanide yield enantioenriched cyanohydrins as versatile chiral building blocks. Next to HCN, volatile organic cyanide sources are usually used. Among them, cyanoformates are more attractive on technical scale than TMSCN for cost reasons, but catalytic productivity is usually lower. Here, the development of a new strategy for cyanations is described, in which this activity disadvantage is overcome. A Lewis acidic Al center cooperates with an aprotic onium moiety within a remarkably robust bifunctional Al–F–salen complex. This allowed for unprecedented turnover numbers of up to 10⁴. DFT studies suggest an unexpected unique trimolecular pathway in which the ammonium bound cyanide attacks the aldehyde, which itself is activated by the carbonyl group of the cyanoformate binding to the Al center. In addition, a novel practical carboxycyanation method was developed that makes use of KCN as the sole cyanide source. The use of a pyrocarbonate as carboxylating reagent provided the best results.