Cyclic RGD peptidomimetics containing 4- and 5-amino-cyclopropane pipecolic acid (CPA) templates as dual α_Vβ₃ and α₅β₁ integrin ligands

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• 作者：Lorenzo Sernissi^a ; Andrea Trabocchi^a ; Dina Scarpi^a ; Francesca Bianchini^b ; Ernesto G. Occhiato^a ; ^{ernesto.occhiato@unifi.it" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Synthesis ; 2 ; 3-Methanopipecolic acids ; Peptidomimetics ; Ligands ; Integrins
• 刊名：Bioorganic & Medicinal Chemistry
• 出版年：2016
• 出版时间：15 February 2016
• 年：2016
• 卷：24
• 期：4
• 页码：703-711
• 全文大小：941 K

文摘

4-Amino- and 5-amino-cyclopropane pipecolic acids (CPAs) with cis relative stereochemistry between the carboxylic and amino groups were used as templates to prepare cyclic peptidomimetics containing the RGD sequence as possible integrin binders. The peptidomimetic c(RGD8) built on the 5-amino-CPA displayed an inhibition activity (IC₅₀ = 2.4 nM) toward the α_vβ₃ integrin receptor (expressed in M21 human melanoma cell line) comparable to that of the most potent antagonists reported so far and it was ten times more active than the corresponding antagonist c(RGD7) derived from the isomeric 4-amino-CPA. Both compounds were also nanomolar ligands of the α₅β₁ integrin (expressed in human erythroleukemia cell line K562). These results suggest that the CPA-derived templates are suitable for the preparation of dual α_vβ₃ and α₅β₁ ligands to suppress integrin-mediated events as well as for targeted drug delivery in cancer therapy.