Abstract
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.
Highlights
In the last decades, a major challenge in cancer chemotherapy has been the discovery of a “magic bullet” to kill tumors without affecting the healthy tissues, through highly selective treatments[1,2]
We have reported the synthesis and biological evaluation of a small library of isoxazoline-based RGD mimetics where the pharmacophores were mimicked by malonic acid and aniline moieties[18]
To gain further information about the agonist/antagonist role of our peptidomimetic integrin ligands and to verify the effect on intracellular signalling, we investigated the effect of most active compounds 17b and 24 on fibronectin-induced phosphorylation of ERK1/2 in K562 cells, which express α5β1 integrin
Summary
A major challenge in cancer chemotherapy has been the discovery of a “magic bullet” to kill tumors without affecting the healthy tissues, through highly selective treatments[1,2]. Among the number of different receptors and proteins involved in tumor physiology, αvβ[3] and α5β1 integrins are highly expressed on activated endothelial cells in several tumors, playing predominant roles in tumor-induced angiogenesis and growth[5] For this reason, peptides and peptidomimetics designed to mimic the recognition sequence RGD (Arg-Gly-Asp)[6], present in the extracellular endogenous ligands of these receptors, have received great attention as targeting motives[7]. Peptides and peptidomimetics designed to mimic the recognition sequence RGD (Arg-Gly-Asp)[6], present in the extracellular endogenous ligands of these receptors, have received great attention as targeting motives[7] Their exploitation as therapeutic tools, per se, is still an option but some recent unsatisfactory results[8] prompted the researchers to turn their attention towards the possible use of these ligands as shuttles for selective delivery of therapeutic payloads and diagnostics[9]. The purpose of this investigation is the synthesis of a variety of discretely sized ligand-linker systems to demonstrate the broad utility of the isoxazoline ligands for diverse and efficient bioconjugation strategies in drug and diagnostic tumor homing
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
