The cyclo[DKP-isoDGR] peptidomimetics 2-5, containing bifunctional diketopiperazine (DKP) scaffolds that differ in the configuration of the two DKP stereocenters and in the substitution at the DKP nitrogen atoms, were prepared and examined in vitro in competitive binding assays with purified αv β3 and αv β5 integrin receptors. IC50 values ranged from low nanomolar (ligand 3) to submicromolar with αv β3 integrin. The biological activities of ligands cyclo[DKP3-RGD] 1 and cyclo[DKP3-isoDGR] 3, bearing the same bifunctional DKP scaffold and showing similar αV β3 integrin binding values, were compared in terms of their cellular effects in human U373 glioblastoma cells. Compounds 1 and 3 displayed overlapping inhibitory effects on the FAK/Akt integrin activated transduction pathway and on integrin-mediated cell infiltration processes, and qualify therefore, despite the different RGD and isoDGR sequences, as integrin antagonists. Both compounds induced apoptosis in glioma cells after 72 hour treatment.

Alzheimer's disease is a neurodegenerative disorder that is linked to oligomerization and fibrillization of different amyloid β‐peptide isoforms. Among these amyloid peptides, Aβ1–42 is considered the most aggregative and neurotoxic species. We report herein the synthesis of four β‐sheet mimics composed of a peptidomimetic arm based on a 5‐amino‐2‐methoxy benzhydrazide derivative, a 2,5‐diketopiperazine scaffold (either cis‐DKP or trans‐DKP) and a tetrapeptide sequence (either Gly‐Val‐Val‐Ile, GVVI, or Lys‐Leu‐Val‐Phe, KLVF). The derivatives containing the cis‐DKP were shown by NMR and computational studies to adopt a stable β‐hairpin conformation in solution, whereas the trans‐DKP scaffold promoted the formation of extended structures. The activity of these compounds in modulating the aggregation of Aβ1–42 peptide was investigated by conducting Thioflavin T fluorescence assays to measure the kinetics of aggregation. Capillary electrophoresis (CE) and transmission electron microscopy (TEM) were then used to monitor the formation of small soluble Aβ oligomers and higher molecular weight and insoluble Aβ aggregates, respectively. As a result, small hairpin mimics containing the cis‐DKP scaffold were found to prevent the formation of small Aβ1–42 oligomeric and neurotoxic species.