Browsing by Author "Pfeuffer, Thomas"

In order to contribute to a rational design of optimised protease inhibitors which can covalently block the nucleophilic amino acids of the proteases' active sites, we have chosen three model compounds (aziridine 1, oxirane 2 and acceptor-substituted olefin 3) for the examination of their electron-density distribution. Therefore, high-resolution low temperature (9, 27 and 100 K) X-ray diffraction experiments on single-crystals were carried out with synchrotron and conventional X-radiation. It could be shown by the analysis of the electron density using mainly Bader's Theory of Atoms in Molecules, Volkov's EPMM method for interaction energies, electrostatic potentials and Gatti's Source Function that aziridine l is most suitable for drug design in this field. A regioselective nucleophilic attack at carbon atom C1 could be predicted and even hints about the reaction's stereoselectivity could be obtained. Moreover, the comparison between two data sets of aziridine 1 (conventional X-ray source vs. synchrotron radiation) gave an estimate concerning the reproducibility of the quantitative results.

Three types of synthesised compounds, the aziridine 1, the epoxide 2 and the acceptor-substituted olefin 3, were chosen as model compounds for electrophilic building blocks, which can covalently block the nucleophilic amino acids of the active sites of proteases (Cys in cysteine proteases or Asp in aspartate proteases). In order to rationally design optimised inhibitors and to understand the differences in inhibition properties of the scrutinised building blocks their structural and electronic properties were studied by ultra-high resolution X-ray diffraction and ab initio calculations to yield the experimental electron-density distribution. It could be shown that the carbon atom C1 of the three-membered heterocycle is the preferred electrophilic centre for attack of the nucleophiles, which is consistent with the results of corresponding chemical experiments with sulfur and oxygen nucleophiles. ((c) Wiley-VCH Verlag GmbH & Co.