Mechanistic studies of melanogenesis: the influence of N‐substitution on dopamine quinone cyclization

Abstract

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.

Dopamine- and tyramine-based derivatives of triazenes: Activation by tyrosinase and implications for prodrug design

“…Our results are consistent with recent studies that show that in urea or carbamate derivatives of dopamine the nitrogen atom is not sufficiently nucleophilic to effect the necessary cyclization that results in release of the antitumour agent [21,22]. …”

Biosynthesis, degradation and pharmacological importance of the fatty acid amides

“…NAcetyldopamine can serve as a substrate for tyrosinase; thus, the long-chain N-acyldopamines could also be oxidized to a quinone by this enzyme [46]. N-Acetylnoradrenaline is a known human metabolite [47] suggesting that N-acetyldopamine and the longer-chain Nacyldopamines could serve as substrates for dopamine β-monooxygenase.…”

ortho-Quinone amines and derivatives: the influence of structure on the rates and modes of intramolecular reaction

“…In contrast to the urea 44, the thiourea 47 cyclises (k d 1.7 s -1 at pH 8.0) to give the bicyclic derivative 48. 3 Clearly the thiourea suphur is a good nucleophile and the rate of seven-membered ring formation is comparable to that observed for the corresponding secondary amines 33 (Table 3). …”

“…The amide 43 and the urea 44 showed no tendency to cyclise and were stable over the pulse radiolysis timescale. 3 However, combined oximetry and spectrophotometry studies showed evidence of first order isomerisation, with well-defined isosbestic points, giving the para-quinomethanes 45 and 46. These ortho-quinone to paraquinomethane rearrangements were found to have rate constants k d ≈ 0.004 s -1 (amide) and k d ≈ 0.0002 s -1 (urea) at pH 7.4.…”

“…1 In particular we have generated reactive ortho-quinones by (i) tyrosinase oxidation of catechols 2 and phenols 3, 2,3 (ii) chemical oxidation of catechols 2 using 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) or dianisyltellurium oxide (DAT), 4,5 and (iii) disproportionation of semi-quinones 4, formed by pulse radiolysis of catechol solutions (Scheme 1). 6 The chemistry of the formation and reactions of these ortho-quinones 1 has been monitored by UV-Vis and 1 H NMR spectroscopy and the use of pulse radiolysis has enabled us to study reactive intermediates with very short half-lives (10 ms -10 s).…”