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Interpreting the Activity of Metastasis-Promoting PRL-3 Through the Total Synthesis of Phosphatidylinositol Analogues

Fahs, Sara

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Abstract

The discovery of phosphatidylinositol-phosphates (PIPn) within cell membranes, in the early 1950’s, ignited the interest in their biological roles, and soon after scientific evidence proposed their tight association with processes involving cell signaling, cell adhesion, polarization and migration, as well as membrane trafficking and oncogenesis. PRL-3, an oncogenic phosphatase, has been recently shown to adopt phosphatidylinositol (4,5) bisphosphate (PI(4,5)P2) as a natural substrate, through which it orchestrates several hallmarks of cancer, culminating in metastasis. Therefore, the PIPn-metabolizing enzyme PRL-3 became of great interest in biomedical research. To understand the binding mechanisms of PI(4,5)P2 with PRL-3, the development of synthetic approaches to synthesize analogues of this natural product is paramount. The goal of this work was to develop an approach to synthesize PI(4,5)P2 mimetics with alkylation(s) on the inositol ring. The newly established synthetic route was first tested with the chiral 6-O-methoxy PI(4,5)P2, after many arising synthetic challenges were overcome. The chemical literature is abundant with PI(4,5)P2 analogues bearing thiophosphate groups, different lipid tail composition, and novel functional groups, but none with direct changes to the hydroxyl groups on the inositol ring have been reported so far. Within the resulting collection of novel, inositol-modified analogues, some showed significant biological activity with PRL-3, compared to the lipid tail-modified analogues and the one containing the natural PI(4,5)P2 head group, which were also synthesized as part of this work. These active analogues were specific to PRL-3 as they did not show major activity with other PI(4,5)P2 –metabolizing enzymes. In parallel, in silico shape similarity screening methods were applied using PI(4,5)P2 as a template, to look for specific PRL-3-active small molecule inhibitors. This led to an active compound, which stresses the potential of prediction tools in finding inhibitors for challenging targets. Future applications of the synthesized PI(4,5)P2 analogues can be numerous: investigating the binding requirements of specific PIPn- metabolizing phosphatases, understanding the biology of specific PIPn, designing ligands through in silico and synthetic methods to modulate their interaction, and probing their usefulness in the treatment of diseases.

Item Type: Dissertation
Supervisor: Köhn, Dr. Maja
Date of thesis defense: 17 May 2018
Date Deposited: 19 Oct 2018 12:38
Date: 2018
Faculties / Institutes: The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences
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