Abstract
By dissecting the structure of β-lactam-based ligands, a new series of compounds was designed, synthesized, and evaluated toward integrins αvβ3, α5β1, and α4β1. New selective ligands with antagonist or agonist activities of cell adhesion in the nanomolar range were obtained. The best agonist molecules induced significant adhesion of SK-MEL-24 cells and Saos-2 cells as a valuable model for osteoblast adhesion. These data could lead to the development of new agents to improve cellular osseointegration and bone regeneration. Molecular modeling studies on prototypic compounds and αvβ3 or α5β1 integrin supported the notion that ligand carboxylate fixing to the metal ion-dependent adhesion site in the β-subunit can be sufficient for binding the receptors, while the aryl side chains play a role in determining the selectivity as well as agonism versus antagonism.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Adhesion / drug effects
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Cell Line
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Humans
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Integrin alpha4beta1 / agonists
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Integrin alpha4beta1 / antagonists & inhibitors
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Integrin alpha4beta1 / metabolism
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Integrin alpha5beta1 / agonists
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Integrin alpha5beta1 / antagonists & inhibitors
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Integrin alpha5beta1 / metabolism
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Integrin alphaVbeta3 / agonists
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Integrin alphaVbeta3 / antagonists & inhibitors
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Integrin alphaVbeta3 / metabolism
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Integrins / agonists*
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Integrins / antagonists & inhibitors*
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Integrins / metabolism
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Ligands
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MAP Kinase Signaling System / drug effects
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Models, Molecular
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Molecular Docking Simulation
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Osteoblasts / drug effects
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Structure-Activity Relationship
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beta-Lactams / chemical synthesis
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beta-Lactams / chemistry*
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beta-Lactams / pharmacology*
Substances
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Integrin alpha4beta1
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Integrin alpha5beta1
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Integrin alphaVbeta3
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Integrins
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Ligands
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beta-Lactams