RESUMO
Two novel tyrosinase mediated drug delivery pathways have been investigated for the selective delivery of cytotoxic units to melanocytes from urea and thiourea prodrugs. The synthesis of these prodrugs is reported, as well as oximetry data that illustrate that the targets are substrates for tyrosinase. The stability of each of the prodrugs in (i) phosphate buffer and (ii) bovine serum is discussed, and the urea prodrugs are identified as lead candidates for further studies. Finally, HPLC studies and preliminary cytotoxicity studies in a melanotic and an amelanotic cell line, that illustrate the feasibility of the approach, are presented.
Assuntos
Sistemas de Liberação de Medicamentos/métodos , Melanócitos/efeitos dos fármacos , Melanoma/tratamento farmacológico , Pró-Fármacos/síntese química , Aminofenóis , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Dopamina/análogos & derivados , Ensaios de Seleção de Medicamentos Antitumorais , Humanos , Monofenol Mono-Oxigenase , UreiaRESUMO
The suitability of 4-di(2-chloroethyl)aminoanilino-4-hydroxyphenethylaminomethanone 2 to act as a prodrug for melanocyte-directed enzyme prodrug therapy (MDEPT) is assessed. Thus its synthesis, ability to generate a cytotoxic agent upon exposure to tyrosinase, and stability within different sera are reported. A comparison is made to illustrate that the new urea prodrug 2 is a more suitable candidate for MDEPT than the corresponding carbamate prodrug 1.