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 highlighted structural properties that are advantageous and disadvantageous for efficient oxidation using mushroom tyrosinase. In particular, a sterically undemanding prodrug bis-(2-chloroethyl)amino-4-hydroxyphenylaminomethanone 28 was synthesised and found to be oxidised by mushroom tyrosinase at a superior rate to tyrosine methyl ester, the carboxylic acid of which is the natural substrate for tyrosinase. The more sterically demanding phenyl mustard prodrugs 9 and 10 were oxidised by mushroom tyrosinase at a similar rate to tyrosine methyl ester. In contrast, tyramine chain elongation via heteroatom insertion was detrimental and the rate of mushroom tyrosinase oxidation of phenyl mustard prodrugs 21 and 22 decreased by 10 nanomol/min.
Jordan
A M
AM
Department of Chemistry, University of Reading, Whiteknights, Reading RG6 6AD, UK.
Khan
T H
TH
Malkin
H
H
Osborn
H M
HM
Photiou
A
A
Riley
P A
PA
D000363:Agaricales / Q000201:enzymology; D002219:Carbamates / Q000737:chemistry* / Q000378:metabolism*; D003630:Daunorubicin / Q000008:administration & dosage / Q000737:chemistry; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D008544:Melanocytes / Q000187:drug effects / Q000201:enzymology; D008545:Melanoma / Q000188:drug therapy; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D009150:Mustard Compounds / Q000737:chemistry; D009588:Nitrogen Mustard Compounds / Q000008:administration & dosage / Q000737:chemistry; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry* / Q000378:metabolism* / Q000494:pharmacology; D013329:Structure-Activity Relationship
C435819:(2'-(3'',4''-dihydroxyphenyl)ethyl)carbamic acid p-(bis-2-chloroethylamino)phenyl ester; C435818:(2'-(4''-hydroxyphenyl)ethyl)carbamic acid p-(bis-2-chloroethylamino)phenyl ester; D002219:Carbamates; D009150:Mustard Compounds; D009588:Nitrogen Mustard Compounds; D011355:Prodrugs; C012128:CB 3034; D014442:Monophenol Monooxygenase; D003630:Daunorubicin