title: Synthesis of diacylated γ-glutamyl-cysteamine prodrugs, and in vitro evaluation of their cytotoxicity and intracellular delivery of cysteamine.
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.
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK.
authors.forename: Lisa
authors.initials: L
authors.lastname: Frost
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK.
authors.forename: Pratap
authors.initials: P
authors.lastname: Suryadevara
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Cannell
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK.
authors.forename: Paul W
authors.initials: PW
authors.lastname: Groundwater
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Hambleton
authors.affiliation: Sunderland Pharmacy School, University of Sunderland, Sunderland, SR1 3SD, UK. Electronic address: roz.anderson@sunderland.ac.uk.
authors.forename: Rosaleen J
authors.initials: RJ
authors.lastname: Anderson
mesh_terms: D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D003543:Cysteamine / Q000008:administration & dosage* / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D003554:Cystinosis / Q000188:drug therapy; D006801:Humans; D011355:Prodrugs / Q000008:administration & dosage* / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics
chemical_list: D011355:Prodrugs; D003543:Cysteamine
keywords: Cysteamine; Cystine; Drug targeting; Nephropathic cystinosis; Prodrug; γ-glutamyl transpeptidase