Electron-Density Determination of Electrophilic Building Blocks as Model Compounds for Protease Inhibitors

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Abstract

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.(© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2007)