Side chain effect in the modulation of αvβ3/α5β1 integrin activity via clickable isoxazoline-RGD-mimetics: development of molecular delivery systems

Autor: Monica Civera, Alessandra Tolomelli, Laura Belvisi, Santi Spampinato, Samantha Deianira Dattoli, Monica Baiula, Lucia Ferrazzano, Dario Corbisiero, Eleonora Potenza
Přispěvatelé: Ferrazzano L., Corbisiero D., Potenza E., Baiula M., Dattoli S.D., Spampinato S., Belvisi L., Civera M., Tolomelli A.
Jazyk: angličtina
Rok vydání: 2020
Předmět:
0301 basic medicine
Agonist
Magnetic Resonance Spectroscopy
MAP Kinase Signaling System
Stereochemistry
medicine.drug_class
Peptidomimetic
Green Fluorescent Proteins
Integrin
lcsh:Medicine
Organic chemistry
Medicinal chemistry
Conjugated system
Ligands
Article
03 medical and health sciences
0302 clinical medicine
Cell Adhesion
medicine
Side chain
Animals
Humans
Chemical synthesis
Bovine serum albumin
lcsh:Science
Cell adhesion
Multidisciplinary
biology
Chemistry
lcsh:R
Isoxazoles
Hydrogen-Ion Concentration
Integrin alphaVbeta3
Chemical biology
Fibronectins
Molecular Docking Simulation
030104 developmental biology
030220 oncology & carcinogenesis
biology.protein
Phosphorylation
lcsh:Q
Cattle
integrins
adhesion
isoxazoline
RGD-mimetics
Peptidomimetics
K562 Cells
Oligopeptides
Integrin alpha5beta1
Zdroj: Scientific Reports
Scientific Reports, Vol 10, Iss 1, Pp 1-19 (2020)
Popis: Construction of small molecule ligand (SML) based delivery systems has been performed starting from a polyfunctionalized isoxazoline scaffold, whose αvβ3 and α5β1 integrins’ potency has been already established. The synthesis of this novel class of ligands was obtained by conjugation of linkers to the heterocyclic core via Huisgen-click reaction, with the aim to use them as “shuttles” for selective delivery of diagnostic agents to cancer cells, exploring the effects of the side chains in the interaction with the target. Compounds 17b and 24 showed excellent potency towards α5β1 integrin acting as selective antagonist and agonist respectively. Further investigations confirmed their effects on target receptor through the analysis of fibronectin-induced ERK1/2 phosphorylation. In addition, confocal microscopy analysis allowed us to follow the fate of EGFP conjugated α5β1 integrin and 17b FITC-conjugated (compound 31) inside the cells. Moreover, the stability in water solution at different values of pH and in bovine serum confirmed the possible exploitation of these peptidomimetic molecules for pharmaceutical application.
Databáze: OpenAIRE
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