Design, synthesis and structural evaluation of peptidomimetics towards foldamers, PNAs and non covalent inhibitors of the 20S proteasome

摘要

The first part of the project, which has been done at the university of Regensburg from November 2005 to October 2007, consisted in a stereoselective synthesis of sugar-like delta-amino acid. This amino acid was a suitable building block for the synthesis of an alpha-delta-pentapetide and an alpha-delta-heptapeptide containing a sequence of Phe and our building block. Conformational studies about these peptides showed the ability of our building block to induce a secondary structure in the synthesised alpha-delta-peptides, in particular an extended helix structure. In addition, the same furanoic scaffold, has been used for the synthesis of some PNA precursor containing thymine and adenine as nucleobases. The second part of the project, which has been done at the univeristy of Paris Sud from November 2007 to october 2008, consisted in the synthesis of peptidomimetics as non covalent inhibitors of 20S proteasome. Using docking methodology, a small library of molecules were design: the most promising molecules were then synthesised, showing an inhibitory activity of the proteasome in a micromolar range.