Honors Theses

Date of Award

5-2025

Document Type

Undergraduate Thesis

Degree Name

BS

Department

Biomedical Sciences

Faculty Mentor

David Forbes

Advisor(s)

Padmamalini Thulasiraman, Hans Schanz

Comments

This research explores the development of selective inhibitors targeting protein phosphatase 5 (PP5), a serine/threonine phosphatase implicated in apoptosis. PP5 negatively regulates tumor suppressors such as p53 and the glucocorticoid receptor (GR), suppressing antiproliferative signaling and enhancing tumor survival under stress conditions like hypoxia. The study aims to create norcantharidin-based derivatives conjugated with folic acid (FA), exploiting the overexpression of folate receptors in certain cancers for targeted drug delivery. Initial synthetic efforts were hindered by folic acid’s poor solubility, prompting a shift toward exploring norcantharidin’s reactivity and ring-opening behavior. Further selectivity was introduced using cinchona alkaloids to catalyze stereoselective ring-opening, generating enantiomerically enriched prodrugs. Biological testing using DiFMUP assays revealed that stereochemistry significantly impacts potency, with cinchonine-derived analogs demonstrating stronger PP5 inhibition than their cinchonidine counterparts. Upon ring-opening, the opportunity for the carboxylic acid or ester moiety to epimerize existed. COSY NMR confirmed that the substituents of both cinchona alkaloid products are in the exo conformation.

Additionally, the study highlights norcantharidin’s synthetic versatility and proposes modular scaffold modifications to improve pharmacological properties. Combining folic acid targeting and stereoselective synthesis establishes a promising platform for developing PP5-selective anticancer therapeutics. These findings lay the groundwork for future optimization of norcantharidin-based drug candidates with improved tumor selectivity, potency, and synthetic feasibility. 5

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