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 ∼ 2.5 × 102/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.