Mechanistic studies of melanogenesis: the influence of N-substitution on dopamine quinone cyclization.
The influence of side-chain structure on the mode of reaction of ortho-quinone amines has been investigated with a view, ultimately, to developing potential methods of therapeutic intervention by manipulating the early stages of melanogenesis. Four N-substituted dopamine derivatives have been prepared and quinone formation studied using pulse radiolysis and tyrosinase-oximetry. Ortho-quinones with an amide or urea side chain were relatively stable, although evidence for slow formation of isomeric para-quinomethanes was observed. A thiourea derivative cyclized fairly rapidly (k = 1.7/s) to a product containing a seven-membered ring, whereas a related amidine gave more rapidly (k approximately 2.5 x 10(2)/s) a stable spirocyclic product. The results suggest that cyclization of amides, ureas and carbamates (NHCO-X; X = R, NHR or OR) does not occur and is not, therefore, a viable approach to the formation of tyrosinase-activated antimelanoma prodrugs. It is also concluded that for N-acetyldopamine spontaneous ortho-quinone to para-quinomethane isomerization is slow.
Borovansky
Jan
J
Department of Biochemistry, 1st Faculty of Medicine, Charles University, U.nemocnice 5, 128 53 Prague 2, Czech Republic.
Edge
Ruth
R
Land
Edward J
EJ
Navaratnam
Suppiah
S
Pavel
Stan
S
Ramsden
Christopher A
CA
Riley
Patrick A
PA
Smit
Nico P M
NP
D000364:Agaricus / Q000201:enzymology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000627:therapeutic use; D004298:Dopamine / Q000031:analogs & derivatives* / Q000737:chemistry; D005656:Fungal Proteins / Q000737:chemistry*; D007536:Isomerism; D008543:Melanins / Q000138:chemical synthesis* / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy / Q000201:enzymology; D015394:Molecular Structure; D014442:Monophenol Monooxygenase / Q000737:chemistry*; D009363:Neoplasm Proteins / Q000737:chemistry; D010084:Oxidation-Reduction; D011355:Prodrugs / Q000737:chemistry
D000970:Antineoplastic Agents; D005656:Fungal Proteins; D008543:Melanins; D009363:Neoplasm Proteins; D011355:Prodrugs; C104705:dopamine quinone; D014442:Monophenol Monooxygenase; D004298:Dopamine