Click-Chemistry-Derived Triazole Ligands of Arginine−Glycine−Aspartate (RGD) Integrins with a Broad Capacity To Inhibit Adhesion of Melanoma Cells and Both in Vitro and in Vivo Angiogenesi

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• 作者：Andrea Trabocchi ; Gloria Menchi ; Nicoletta Cini ; Francesca Bianchini ; Silvia Raspanti ; Anna Bottoncetti ; Alberto Pupi ; Lido Calorini ; Antonio Guarna
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：October 14, 2010
• 年：2010
• 卷：53
• 期：19
• 页码：7119-7128
• 全文大小：1063K
• 年卷期：v.53,no.19(October 14, 2010)
• ISSN：1520-4804

文摘

A click chemistry approach was applied for the discovery of triazole-based arginine−glycine−aspartate (RGD) mimetics by Cu(I)-catalyzed 1,3-dipolar alkyne−azide coupling reaction, which showed binding affinity properties toward α_vβ₃/α_vβ₅ integrins. Biological assays showed compound 18 capable of binding α_vβ₃ integrin with nanomolar affinity according to a two-sites model, and molecular modeling studies revealed a peculiar π-stacking interaction between the triazole ring and Tyr178 side chain. Accordingly, compound 18 inhibited the adhesion of integrin-expressing human melanoma cells to RGD-containing proteins of the extracellular matrix, such as vitronectin, fibronectin, and osteopontin, and also angiogenesis in in vitro and in vivo experimental models. The relevant biological effects exerted by compound 18 suggest its potential application as an antiangiogenic agent in the diagnosis and therapy of tumors where α_vβ₃ integrin expression is up-regulated.