ORGN 251 |
| A new powerful strategy is emerging for replacing the peptide bond with a very effective mimic: the streogenic trifluoroethylamine function. Indeed, a trifluoroethyl group can replace the carbonyl of an amide and generate a metabolically stable, non-basic amine that maintains the excellent hydrogen bond of an amide. This strategy was first proposed by our research group, and was used to replace both a glycine amide bond and a malonamide of a partially modified retropeptide. The main properties featured by the trifluoroethylamino group are: (1) low NH basicity, (2) a CH(CF3)NHCH backbone angle close to 120°, (3) a C-CF3 bond substantially isopolar with the C=O, (4) structural analogy with the tetrahedral proteolytic transition state. Furthermore, the sp3 hybridization of all the atoms forming the stereogenic trifluoroethylamine moiety is expected to allow a better orientation of the atoms in the receptors active sites, thus optimizing the energetically favourable interactions. Some application of this strategy in the realm of drug discovery will be presented. |
|
Peptide Bond Isosteres
8:10 AM-12:00 PM, Monday, 11 September 2006 Moscone Center -- Room 135, Oral
Division of Organic Chemistry |