Melanocyte-directed enzyme prodrug therapy (MDEPT): Development of second generation prodrugs for targeted treatment of malignant melanoma

Evaluation of second generation prodrugs for MDEPT, by oximetry, has highli ghted structural properties that are advantageous and disadvantageous for e fficient oxidation using mushroom tyrosinase. In particular, a sterically u ndemanding prodrug bis-(2-chloroethyl)amino-4-hydroxyphenylaminomethanone 2 8 was synthesised and found to be oxidised by mushroom tyrosinase at a supe rior rate to tyrosine methyl ester, the carboxylic acid of which is the nat ural substrate for tyrosinase. The more sterically demanding phenyl mustard prodrugs 9 and 10 were oxidised by mushroom tyrosinase at a similar rate t o tyrosine methyl ester. In contrast, tyramine chain elongation via heteroa tom insertion was detrimental and the rate of mushroom tyrosinase oxidation of phenyl mustard prodrugs 21 and 22 decreased by 10 nanomol/min. (C) 2001 Elsevier Science Ltd. All rights reserved.