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Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine

Frost, Lisa, Suryadevara, Pratap, Cannell, Stephanie, Groundwater, Paul, Hambleton, Paul and Anderson, Rosaleen (2015) Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine. European Journal of Medicinal Chemistry, 109. pp. 206-215. ISSN 0009-4374

Item Type: Article

Abstract

To overcome the major disadvantages of cysteamine, the only registered treatment for the rare genetic disease cystinosis, nine prodrugs of γ-glutamyl-cysteamine (4) were synthesized for evaluation. Esterification of the thiol conferred oxidative stability, while sufficient lipophilicity for oral bioavailability was achieved by acylation of the α-carboxyl group of γ-glutamyl-cysteamine (4). Low cytotoxicity was observed in cultured HaCaT keratinocytes using the MTT assay, with EC50 values higher than or similar to that of cysteamine. Successful uptake of the esterified prodrugs and the subsequent release of cysteamine into cultured human proximal tubule epithelial cells were demonstrated using CMQT derivatisation and HPLC with UV detection. These prodrugs show potential as novel delivery vehicles of cysteamine to improve the treatment of the genetic disorder nephropathic cystinosis.

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Depositing User: Paula Normington

Identifiers

Item ID: 5904
Identification Number: https://doi.org/10.1016/j.ejmech.2015.12.027
ISSN: 0009-4374
URI: http://sure.sunderland.ac.uk/id/eprint/5904
Official URL: https://www.sciencedirect.com/science/article/abs/...

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Catalogue record

Date Deposited: 22 Jan 2016 11:10
Last Modified: 30 Sep 2020 11:04

Contributors

Author: Lisa Frost
Author: Pratap Suryadevara
Author: Stephanie Cannell
Author: Paul Groundwater
Author: Paul Hambleton
Author: Rosaleen Anderson

University Divisions

Faculty of Health Sciences and Wellbeing

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Sciences

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