Integrins are a large family of heterodimeric transmembrane glycoproteins involved in the attachment of a cell to the extracellular matrix (ECM). Alterations or aberrations in integrin-mediated cell adhesion have been connected with the pathogenesis of several diseases. In particular, alphaVbeta3 integrins, which are involved in many processes such as tumour proliferation and metastasis, bind to a wide number of ECM components through recognition of the Arg-Gly-Asp (RGD) tripeptidic sequence. This sequence is also essential for the binding of alpha5beta1 integrin to fibronectin, which has been unambiguously recognized as proangiogenic receptor. Therefore, antagonists of both integrins, block the pathway of angiogenesis. The need for antagonists with high bioavailability and low molecular weight has prompted several research groups to develop small constrained non-peptidic molecules mimicking the RGD motif. Most of the structures proposed so far share a common pattern, consisting of a polyfunctionalized rigid core, linked to appendages corresponding to arginine and aspartic acid side chains. Recently the design and application of novel synthetic pathways leading to constrained non-peptidic RGD mimetics, containing heterocyclic scaffolds or unusual beta-aminoacids, has been developed. Modifications have been addressed to the nature and length of the arginine and aspartate mimicking branches. Moreover, the blockade of fibronectin-mediated cell adhesion of these novel integrin dual antagonists has been tested, to verify if their activity could be synergistically effective in preventing angiogenesis. Some derivatives showed a promising binding affinity and could represent lead compounds for drug development.
Synthesis and Biological Evaluation of Nonpeptide alpha-v-beta-3/alpha-5-beta-1 Integrin Dual Antagonists
TOLOMELLI, ALESSANDRA
2008
Abstract
Integrins are a large family of heterodimeric transmembrane glycoproteins involved in the attachment of a cell to the extracellular matrix (ECM). Alterations or aberrations in integrin-mediated cell adhesion have been connected with the pathogenesis of several diseases. In particular, alphaVbeta3 integrins, which are involved in many processes such as tumour proliferation and metastasis, bind to a wide number of ECM components through recognition of the Arg-Gly-Asp (RGD) tripeptidic sequence. This sequence is also essential for the binding of alpha5beta1 integrin to fibronectin, which has been unambiguously recognized as proangiogenic receptor. Therefore, antagonists of both integrins, block the pathway of angiogenesis. The need for antagonists with high bioavailability and low molecular weight has prompted several research groups to develop small constrained non-peptidic molecules mimicking the RGD motif. Most of the structures proposed so far share a common pattern, consisting of a polyfunctionalized rigid core, linked to appendages corresponding to arginine and aspartic acid side chains. Recently the design and application of novel synthetic pathways leading to constrained non-peptidic RGD mimetics, containing heterocyclic scaffolds or unusual beta-aminoacids, has been developed. Modifications have been addressed to the nature and length of the arginine and aspartate mimicking branches. Moreover, the blockade of fibronectin-mediated cell adhesion of these novel integrin dual antagonists has been tested, to verify if their activity could be synergistically effective in preventing angiogenesis. Some derivatives showed a promising binding affinity and could represent lead compounds for drug development.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
