New β-Lactam Derivatives Modulate Cell Adhesion and Signaling Mediated by RGD-Binding and Leukocyte Integrins

被引：45

作者：

Baiula, Monica ^{[1
]}

Galletti, Paola ^{[2
]}

Martelli, Giulia ^{[2
]}

Soldati, Roberto ^{[2
]}

Belvisi, Laura ^{[3
]}

Civera, Monica ^{[3
]}

Dattoli, Samantha Deianira ^{[1
]}

Spampinato, Santi Mario ^{[1
]}

Giacomini, Daria ^{[2
]}

机构：

[1] Univ Bologna, Dept Pharm & Biotechnol, Via Irnerio 48, I-40126 Bologna, Italy

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

[3] Univ Milan, Dept Chem, Via Golgi 19, I-20133 Milan, Italy

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2016年 / 59卷 / 21期

关键词：

SMALL-MOLECULE AGONIST; ALPHA(4)BETA(1) INTEGRIN; CONFORMATIONAL CONTROL; BIOLOGICAL EVALUATION; STRUCTURAL BASIS; AMINO-ACIDS; ANTAGONISTS; INHIBITORS; LIGANDS; POTENT;

D O I：

10.1021/acs.jmedchem.6b00576

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A novel series of beta-lactam derivatives that was designed and synthesized to target RGD-binding and leukocyte integrins is reported. The compound library was evaluated by investigating the effects on integrin-mediated cell adhesion and cell signaling in cell lines expressing alpha(v)beta(3), alpha(v)beta(5), alpha(v)beta(6), alpha(5)beta(1), alpha(IIb)beta(3), alpha(4)beta(1), and alpha(1)beta(2) integrins. SAR analysis of the new series of azetidinones enabled the recognition of structural elements associated with integrin selectivity. We obtained selective and potent agonists that could induce cell adhesion and promote cell signaling mediated by alpha(v)beta(3), alpha(v)beta(5), alpha(5)beta(1), or alpha(4)beta(1) integrin, and antagonists for the integrins alpha(v)beta(3) and alpha(5)beta(1), as well as alpha(4)beta(1) and alpha(1)beta(2), preventing the effects elicited by the respective endogenous agonists.

引用

页码：9721 / 9742

页数：22

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