In the course of our drug development program, we have been interested to the synthesis of small peptidomimetics1 of the RGD (Arg-Gly-Asp) motif, present in a wide number of extracellular matrix (ECM) proteins.2 These ligands bind to alpha-v-beta-3 and alpha-5-beta-1 integrins, a large family of heterodimeric transmembrane glycoproteins, involved in the pathogenesis of several diseases, such as atheroschlerosis, osteoporosis, cancer and a variety of inflammatory disorders. Design and synthesis of new enantiopure non proteinogenic amino acids represent a central issue for chemists working in this wide research area. In the field of organic and medicinal chemistry, the preparation of small heterocyclic rings by means of simple and efficient routes is receiving ever increasing attention.3 In this context, substituted isoxazolidines or dihydropyrroles constitute versatile synthetic intermediates and may be exploited as effective scaffolds to induce the proper orientation to Asp and Arg mimicking chains. Small libraries of peptidomimetics have been designed, synthesized and tested and some derivatives resulted to be potent ligand for both alpha-v-beta-3 and alpha-5-beta-1 integrins, being regarded as a dual inhibitors. This activity could be synergistically effective in preventing angiogenesis by blocking different pathways of the blood vessel formation in tumors.
Dehydro-beta-amino acids as scaffolds for the preparation of alpha-v-beta-3, alpha-5-beta-1 and alpha-4-beta-1 integrin ligands
TOLOMELLI, ALESSANDRA;GENTILUCCI, LUCA;MOSCONI, ELISA;VIOLA, ANGELO;BAIULA, MONICA;SPAMPINATO, SANTI MARIO;
2011
Abstract
In the course of our drug development program, we have been interested to the synthesis of small peptidomimetics1 of the RGD (Arg-Gly-Asp) motif, present in a wide number of extracellular matrix (ECM) proteins.2 These ligands bind to alpha-v-beta-3 and alpha-5-beta-1 integrins, a large family of heterodimeric transmembrane glycoproteins, involved in the pathogenesis of several diseases, such as atheroschlerosis, osteoporosis, cancer and a variety of inflammatory disorders. Design and synthesis of new enantiopure non proteinogenic amino acids represent a central issue for chemists working in this wide research area. In the field of organic and medicinal chemistry, the preparation of small heterocyclic rings by means of simple and efficient routes is receiving ever increasing attention.3 In this context, substituted isoxazolidines or dihydropyrroles constitute versatile synthetic intermediates and may be exploited as effective scaffolds to induce the proper orientation to Asp and Arg mimicking chains. Small libraries of peptidomimetics have been designed, synthesized and tested and some derivatives resulted to be potent ligand for both alpha-v-beta-3 and alpha-5-beta-1 integrins, being regarded as a dual inhibitors. This activity could be synergistically effective in preventing angiogenesis by blocking different pathways of the blood vessel formation in tumors.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.