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Synthèse d'inhibiteurs potentiels de glycosidases et d'urées cycliques de conformation restreinte

Abstract : glycosidases and cyclic ureas of restricted conformation carried by a piperidine, agents allowing the control of the proliferation of cancer cells. These two families of compounds were prepared starting from a key piperidine intermediate, obtained by intramolecular Mannich reaction between the ethyl trans-4-oxo-2-butenoate and a protected β-aminoketone in the form of on acetal. Initially, we synthesised a tri-hydroxylated indolizidine in racemic and optically pure series in 10 steps. In order to increase the inhibiting potential of glycosidases, we developed the synthesis of a tetra-hydroxylated indolizidine having an additional hydroxyl moiety on the piperidine, requiring the preparation of the corresponding optically pure protected β-aminoketone. The activities of these two indolizidines previously prepared in racemic and optically pure series were evaluated on six commercially available enzymes. Only the racemic tetra hydroxylated indolizidine proved to be a selective inhibitor of the β-galactosidase of Aspergillus oryzae (Ki 157μM). Then, we synthesised cyclic ureas of restricted conformation by reaction of the key intermediate on various commercially available isocyanates, followed by a highly stereoselective Michael cyclisation. The antiproliferative activity of these new compounds was the subject of an evaluation on three human cell lines, unfortunately they did not appear cytotoxic. Finally, we used the reactivity of the key intermediate to synthesise various types of molecules : cyclic thioureas and compounds with 5 or 6 membered guanidine ring constituting the basic skeleton of a natural product, the cylindrospermopsine.
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  • HAL Id : tel-00718540, version 1


Delphine Baumann. Synthèse d'inhibiteurs potentiels de glycosidases et d'urées cycliques de conformation restreinte. Chimie organique. Université Blaise Pascal - Clermont-Ferrand II, 2007. Français. ⟨NNT : 2007CLF21812⟩. ⟨tel-00718540⟩



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