Effect of electron-withdrawing substituents on the epoxide ring: an experimental and theoretical electron density analysis of a series of epoxide derivatives.

A series of acceptor-substituted epoxide derivatives is scrutinized by means of experimental and theoretical electron-density investigations. Due to the possibility of nucleophilic ring-opening, the epoxide ring is not only a very useful functional group in organic synthesis, but acceptor-substituted epoxides are valuable building blocks for the design of protease inhibitors. Therefore, the electron-density analysis in this work focuses on two main aspects that can contribute to rational drug design: (i) the quantification of the electron-withdrawing substituent effects on the epoxide ring and (ii) the intermolecular interactions involving the epoxide ring in combination with different substituents. It can be shown that the electron-withdrawing properties of the substituents cause an elongation of the C-C bonds in the epoxide rings and the loss of electron density can be measured by an analysis of critical points, atomic charges, and the source function. The different strengths of the substituents are reflected in these properties. Covalent and electrostatic contributions to the intermolecular interactions and thus the lattice energies are depicted on different molecular surfaces.

New cis-configured aziridine-2-carboxylates as aspartic acid protease inhibitors.

A series of 52 cis-configured 1-alkyl-3-phenylaziridine-2-carboxylates were synthesized as new pseudo-irreversible inhibitors of Candida albicans secreted aspartic acid protease 1 (SAP1), SAP2, SAP3, and SAP8. Some of the compounds, which were obtained as diastereomers with S,S- and R,R-configured aziridine rings by Cromwell synthesis of racemic (2R,3S+2S,3R)-dibromophenylpropionic acid ester with amines, followed by ester hydrolysis and coupling to hydrophobic amino acid esters, were separated by preparative HPLC. The absolute configuration of the aziridine ring was assigned by a combination of experimental circular dichroism (CD) investigations and quantum chemical CD calculations. In agreement with previous docking studies, the diastereomers all exhibit similar activity. The compounds were found to be more active against the related mammalian enzyme cathepsin D, presumably due to productive interactions of the N-alkyl substituent with the highly lipophilic S2 pocket. The most active inhibitors (5, 9, 10, 21, and 28), characterized by benzyl, cyclohexylmethyl, tert-butyl, or 1,4-dimethylpentyl moieties at the aziridine nitrogen atom, exhibit k(2nd) values between 500 and 900×10³ M⁻¹ min⁻¹ and K(i) values near or below 1 µM for cathepsin D.

A comparative study on the experimentally derived electron densities of three protease inhibitor model compounds.

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 , oxirane and acceptor-substituted olefin ) 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 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 (conventional X-ray source vs. synchrotron radiation) gave an estimate concerning the reproducibility of the quantitative results.