New prodrugs derived from 6-aminodopamine and 4-aminophenol as candidates for melanocyte-directed enzyme prodrug therapy (MDEPT).
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.
Knaggs
Sarah
S
School of Chemistry, University of Reading, Whiteknights, Reading, UK.
Malkin
Hugh
H
Osborn
Helen M I
HM
Williams
Nana Aba O
NA
Yaqoob
Parveen
P
D000627:Aminophenols; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004298:Dopamine / Q000031:analogs & derivatives; D016503:Drug Delivery Systems / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D008544:Melanocytes / Q000187:drug effects*; D008545:Melanoma / Q000188:drug therapy*; D014442:Monophenol Monooxygenase; D011355:Prodrugs / Q000138:chemical synthesis*; D014508:Urea
D000627:Aminophenols; D011355:Prodrugs; C006532:6-aminodopamine; D014508:Urea; D014442:Monophenol Monooxygenase; C026729:4-aminophenol; D004298:Dopamine