Exploring dipeptide-derived molecular diversity and applications in medicinal chemistry

In the field of peptidomimetic chemistry, small and medium rings derived from peptides are of particular interest owing to their facile access, the chemical and stereochemical diversity of amino acids. In addition, such molecules are potentially useful to constrain intrinsically short linear peptide chains and for mimicking local folded polypeptide structures, such as β-turns.

The 1,3,5-triazepan-2,6-dione system. We have recently developped the 1,3,5-triazepan-2,6-dione platform as a novel, conformationally restricted, and readily accessible class of dipeptidomimetics. The synthesis of this densely functionalized skeleton is achieved in only four steps from a variety of simple linear dipeptide precursors. Molecular and structural diversity can be increased further through post-cyclization appending operations at urea nitrogens.

Figure : X-ray structures of some representative members of the 1,3,5-triazepan-2,6-dione family

Towards Inhibitors of secreted Phospholipase A2 (sPLA2s). Because they are structurally diverse and rapidly accessible in a library format from dipeptides, 1,3,5- triazepan-2,6-diones have a strong potential for use in biological screens. Using an in-silico screening approach, in collaboration with D. Rognan (Fac. Pharma, Illkirch, France), and G. Lambeau (IPMC, Sophia-Antipolis, France), we identified 1,3,5-triazepan- 2,6-diones as inhibitors of group V and group X secreted phospholipase A2 (sPLA2). Our current efforts are directed towards the optimization of these first hits.

Selected Publications : Lena & Guichard, Curr. Org. Chem. 2008, 12, 813-835 ; Muller et al. J. Med. Chem. 2006, 49, 6768 – 6778 ; Schaffner et al. Chem. Commun., 2006, 469-471 ; Lena et al. Chem Eur. J. 2006, 12, 8498-512 ;