Search

The aim of this study was to investigate the transition from non-covalent reversible over covalent reversible to covalent irreversible inhibition of cysteine proteases by making delicate structural changes to the warhead scaffold. To this end, dipeptidic rhodesain inhibitors with different N-terminal electrophilic arenes as warheads relying on the SNAr mechanism were synthesized and investigated. Strong structure–activity relationships of the inhibition potency, the degree of covalency, and the reversibility of binding on the arene substitution pattern were found. The studies were complemented and substantiated by molecular docking and quantum-mechanical calculations of model systems. Furthermore, the improvement in the membrane permeability of peptide esters in comparison to their corresponding carboxylic acids was exemplified. [ABSTRACT FROM AUTHOR]

The stability of N-alkoxypyridine-2(1H)thione as precursors of photochemical alkoxy radicals is enhanced by the blue shift of the broad absorption band at 360 nm. This is achieved by the substitution at the pyridinethione heterocycle.

Femtosecond time-resolved photoionization and photoelectron spectroscopy are used to investigate the excited-state dynamics of the tert-butyl radical, t-[C.sub.4][H.sub.9]. Ab initio calculations of the electronic ground state and a number of electronically excited states are performed in order to understand the shapes and characters of the excited-state potential energy surfaces.

A synthesis for the unsubstituted bicyclo[1.1.0]but-2-ylmethanols from 1,3-butadiene is developed. Solvolyses of their sulfonates took entirely different courses, as the endo compound gave rise exclusively to rearranged products such as cyclopent-3-en-1-ol, while the exo compound underwent only the substitution of the tosylate group with complete retention of the exco-bicyclo[1.1.0]but-2-ylmethyl skeleton.

The accuracy of theoretical approaches to describe electronic absorption spectra of N-(hydroxy)- and N-(methoxy)- derivatives of pyridine-2(1H)-thione and thiazole-2(3H)-thione are examined. Its aim is to identify methods that are applicable for a rational design of new photochemically active oxyl radical precursors.

Accurate association constants of xanthosine and inosine dimers are determined by concentration dependent H NMR experiments, and a structural characterization of individual complexes formed in solution is performed through measurements under slow exchange conditions at very low temperatures. The influence of polar medium on the bonding properties is also estimated and the importance of the various effects is discussed.

An intermolecular hydrogen bonding network establishes the X-ray structure analysis of the aziridinyl peptide EtO-Azi-Gly-OBn indicating the linear conformation adopted in the crystalline state. However, it is concluded that the intramolecular interactions in the crystal are stronger than the intermolecular ones, which for a single molecule would lead to a bent structure.

Abstract Background A number of algorithms for steady state analysis of metabolic networks have been developed over the years. Of these, Elementary Mode Analysis (EMA) has proven especially useful. Despite its low user-friendliness, METATOOL as a reliable high-performance implementation of the algorithm has been the instrument of choice up to now. As reported here, the analysis of metabolic networks has been improved by an editor and analyzer of metabolic flux modes. Analysis routines for expression levels and the most central, well connected metabolites and their metabolic connections are of particular interest. Results YANA features a platform-independent, dedicated toolbox for metabolic networks with a graphical user interface to calculate (integrating METATOOL), edit (including support for the SBML format), visualize, centralize, and compare elementary flux modes. Further, YANA calculates expected flux distributions for a given Elementary Mode (EM) activity pattern and vice versa. Moreover, a dissection algorithm, a centralization algorithm, and an average diameter routine can be used to simplify and analyze complex networks. Proteomics or gene expression data give a rough indication of some individual enzyme activities, whereas the complete flux distribution in the network is often not known. As such data are noisy, YANA features a fast evolutionary algorithm (EA) for the prediction of EM activities with minimum error, including alerts for inconsistent experimental data. We offer the possibility to include further known constraints (e.g. growth constraints) in the EA calculation process. The redox metabolism around glutathione reductase serves as an illustration example. All software and documentation are available for download at http://yana.bioapps.biozentrum.uni-wuerzburg.de. Conclusion A graphical toolbox and an editor for METATOOL as well as a series of additional routines for metabolic network analyses constitute a new user-friendly software for such efforts.

The reaction courses of possible ring-opening reactions accompanied by the attack of a nucleophile for different substituent patterns of the aziridine are examined. The results have helped in understanding the mechanisms of different ring-opening reactions and have explained how the kinetics and thermodynamics of the reaction are affected by substituents, which has predicted substitution patterns that steer the reaction course to either CN or CC bond cleavage.

Keto-enol tautomerization of 3-formylacetylacetone is analyzed by NMR spectroscopy ab initio, and DFT calculations in the gas phase and continuum solvation. The tautomeric distribution of 3-formylacetylacetone is properly reproduced by continuum solvated DFT calculations.

The underlying effects of the inhibition of cysteine proteases are examined by using classical molecular dynamic simulations and combined quantum mechanics/molecular modeling (QM/MM) calculations for the E64c-cathepsin B complex. The results provide insight into the hydrogen bonding network between the enzyme and the E64c, which influenced the stereoselectivity of the subsequent ring opening reaction by governing the distance between the attacking thiolate and the attacked C2 atom of the epoxide ring.

The quantum mechanical/molecular mechanical (QM/MM) hybrid calculations are employed to determine the regiospecificity, as well as the inhibition potency of epoxide- and aziridine-based inhibitors that are involved in the inhibition of various cysteine proteases.

A computer-aided design of new alkoxyl radical precursors is performed which should combine the advantages of N-alkoxypyridine-2(1H)thiones (less reactive radicals) and N-alkoxythiazole-2(3H)thiones (stable with respect of daylight). 18 test candidates were obtained by a systematic variation of the parent compound N-alkoxythiazole-2(3H)thione.

Epoxides, aziridines, and thiiranes are electrophilic building blocks that are widely used in synthetic organic chemistry and also as electrophilic 'warheads' for irreversible peptidic or peptidomimetic cysteine protease inhibitors. The experimental results concerning variations in the reactivities and the regioselectivities and also the different reasons for the increased inhibition potency of three-membered heterocycles containing an acidic substituent are discussed

A set of different sulfur-nitrogen compounds, which contains eight different SN bonds of varying polarity, is employed. The outcomes of the atoms-in-molecules approach are compared with results obtained from the natural bond orbital approach and natural resonance theory.

Cysteine proteases play pivotal roles in many diseases, making them attractive targets for the development of new drugs. The results show that the large enhancement of the inhibition potencies of aziridines at lower pH values results from a strong catalysis even by weak proton donors.

Six-membered monocyclic systems containing second- (B-O) and third-row elements (Al-S) of the periodic table of elements are studied in detail, regarding the energetic order of the electronic states and the planarization energies, which together determine their chemical behavior. Also, how the various kinds of interaction influence the chemistry of this important class of intermediates is analyzed.