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 (2016) 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.

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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.

Item Type: Article
Subjects: Sciences
Divisions: Faculty of Applied Sciences
Faculty of Applied Sciences > Department of Pharmacy Health and Wellbeing
Health Sciences and Wellbeing Beacon
Health Sciences and Wellbeing Beacon > Drug Discovery and Application Workstream
Depositing User: Paula Normington
Date Deposited: 22 Jan 2016 11:10
Last Modified: 19 Sep 2017 16:10
URI: http://sure.sunderland.ac.uk/id/eprint/5904

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