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Evaluation of new succinimide-based small molecules as alphavbeta3 integrin antagonists: from design to preliminary biological testing

Dell’Albani, Arianna
Publication Date
End of Embargo
Supervisor
Loadman, Paul
Shnyder, Steven
Sheldrake, Helen
Keywords
Integrins, Succinamide, Synthesis, Alphavbeta3, Metabolism, isoDGR, RGD, Prodrug, Cyclization, Integrin antagonists
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Creative Commons License
The University of Bradford theses are licenced under a Creative Commons Licence.
Peer-Reviewed
Open Access status
Accepted for publication
Institution
University of Bradford
Department
School of Pharmacy. Faculty of Life Sciences
Awarded
2023
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PhD Thesis
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Abstract
Integrins are a family of cell surface protein receptors consisting of two subunits, called α and β, involved in several biological processes, including regulation of signalling between cells and other cells or ECM. Integrins are overexpressed in diseases, first of all cancer. Being able to bind several ligands which contain the endogenous peptidic motif, RGD, αvβ3 is the most important of the family, associated with angiogenesis and aggressiveness of the tumour. However, molecules designed as antagonists based on RGD have shown partial agonism. This limit may be overpassed by switching from RGD to isoDGR motif. Here, some isoDGR analogues prodrugs have been designed and synthesised, by a multi-step route to obtain the different fragments (isoAsp, Gly and Arg) subsequently connected together [Fig. A.01]. The molecules have been tested in ex-vivo metabolism assay in liver, kidney and tumour tissues. Cytotoxicity has been tested for all compounds in M14 and DLD1 cell lines: no effect was observed in MTT assay. Migration inhibition has been evaluated by performing scratch assay on M14 and DLD1 cell lines. Compound 4 has shown the best migration inhibition, with IC50 = 4.62 ± 1.70 μM at 12h and IC50 = 5.63 ± 1.77 μM at 24h. [Fig A.01] The work made in this project can be used as preliminary evaluation for a deeper investigation in succinamides-based prodrugs as integrins antagonists.
URI
https://bradscholars.brad.ac.uk/handle/10454/20643
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Type
Thesis
Qualification name
PhD
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