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

• Published in: European journal of medicinal chemistry Vol. 109; pp. 206 - 215
• Main Authors: Frost, Lisa, Suryadevara, Pratap, Cannell, Stephanie J., Groundwater, Paul W., Hambleton, Paul A., Anderson, Rosaleen J.
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier Masson SAS 15.02.2016; Elsevier
• Subjects: Cell Line; Cell Survival - drug effects; Chemistry, Medicinal; Cysteamine; Cysteamine - administration & dosage; Cysteamine - adverse effects; Cysteamine - analogs & derivatives; Cysteamine - pharmacokinetics; Cystine; Cystinosis - drug therapy; Drug targeting; Humans; Life Sciences & Biomedicine; Nephropathic cystinosis; Pharmacology & Pharmacy; Prodrug; Prodrugs - administration & dosage; Prodrugs - adverse effects; Prodrugs - chemistry; Prodrugs - pharmacokinetics; Science & Technology; γ-glutamyl transpeptidase; Cysteamine; Drug targeting; Nephropathic cystinosis; γ-glutamyl transpeptidase; Prodrug; Cystine; LOCALIZATION; SPECIFICITY; CARBOXYLESTERASES; TRANSPEPTIDASE; TRANSPORT; DISEASE; gamma-glutamyl transpeptidase; CYSTIC-FIBROSIS; KIDNEY; DERIVATIVES
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2015.12.027

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. [Display omitted] •Prodrugs were synthesized to overcome the major disadvantages of cysteamine.•Prodrugs were targeted to GGT to release cysteamine on the cell surface.•The prodrugs showed low cytotoxicity in an MTT assay in cultured HaCaT cells.•Successful uptake and release of cysteamine was observed in cultured kidney cells.