RESUMO
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.
Assuntos
Cisteamina/análogos & derivados , Cisteamina/administração & dosagem , Pró-Fármacos/administração & dosagem , Pró-Fármacos/química , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Cisteamina/efeitos adversos , Cisteamina/farmacocinética , Cistinose/tratamento farmacológico , Humanos , Pró-Fármacos/efeitos adversos , Pró-Fármacos/farmacocinéticaRESUMO
Compounds containing the naphthoate moiety of Neocarzinostatin chromophore or 2-hydroxynaphthoate have been synthesized and evaluated for cytotoxic activity against a leukemia cell line and a small panel of human-tumor cell lines. Those compounds containing a cyclopentenone moiety were active, with the carbonyl group being essential for biological activity.