Targeting integrins αvβ3 and α5β1 with new β-lactam derivatives

被引：37

作者：

Galletti, Paola ^{[1
]}

Soldati, Roberto ^{[1
]}

Pori, Matteo ^{[1
]}

Durso, Margherita ^{[1
]}

Tolomelli, Alessandra ^{[1
]}

Gentilucci, Luca ^{[1
]}

Dattoli, Samantha Deianira ^{[2
]}

Baiula, Monica ^{[2
]}

Spampinato, Santi ^{[2
]}

Giacomini, Daria ^{[1
]}

机构：

[1] Univ Bologna, Dept Chem G Ciamician, Via Selmi 2, I-40126 Bologna, Italy

[2] Univ Bologna, Dept Pharm & Biotechnol, I-40126 Bologna, Italy

来源：

EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 83卷

关键词：

Lactams; Integrins; Azetidinones; Peptidomimetics; Agonists; Cell adhesion; SMALL-MOLECULE AGONIST; CELL-ADHESION; AMINO ACIDS; ANTAGONISTS; ACTIVATION; PEPTIDOMIMETICS; HOMEOSTASIS; CD11B/CD18; MODULATION; ANTIBODIES;

D O I：

10.1016/j.ejmech.2014.06.041

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

The alpha(v)beta(3) and alpha(5)beta(1) integrins are widely expressed in different cancer types and recognize the tripeptide Arg-Gly-Asp (RGD) motif present in several extracellular matrix proteins. We report here the design, synthesis and biological activity of some new beta-lactam derivatives specifically designed to target integrins. The new molecules contain the azetidinone as the only cyclic framework armed with carboxylic acid and amine terminals spaced from 9 to 14 atoms to switch on recognition by integrins. All tested molecules showed a concentration-dependent enhancement in fibronectin-mediated adhesion of K562 and SK-MEL-24 cells; in particular 1, expressed a higher affinity towards alpha(5)beta(1) integrin (EC50 of 12 nM) and 2 was more selective for integrin alpha(v)beta(3) (EC50 of 11 nM). (C) 2014 Elsevier Masson SAS. All rights reserved.

引用

页码：284 / 293

页数：10

共 45 条

[1]

Aizpurua J. M., 2006, [No title captured], Patent No. [W02006048473, 2006048473, WO2006048473A1]

[2]

Aizpurua J. M., 2012, Eur. Pat. Appl., Patent No. [EP 2407478 A1 20120118, 2407478]

[3] Cyclic RGD β-Lactam Peptidomimetics Induce Differential Gene Expression in Human Endothelial Cells [J].