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    Reactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents.

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    Authors
    Cooksey, C J
    Jimbow, K
    Land, Edward J
    Riley, P A
    Affiliation
    Department of Chemistry, University College London, UK.
    Issue Date
    1992-12
    
    Metadata
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    Abstract
    It may be possible to use the melanogenic pathway as a therapeutic targeting strategy for melanoma, and encouraging clinical pilot studies of 4-hydroxyanisole have led to the search for more active analogue substrates of tyrosinase. A recent study of a range of alkoxy- and alkylthio-phenol analogues of tyrosine has shown that sulphur-containing compounds exhibit different behaviour to that of similar oxygen-containing compounds, indicating modified reactivities of their corresponding tyrosinase-induced o-quinones towards crucial cellular targets, in particular, thiols. We have therefore examined by pulse radiolysis the reactivities of a group of unstable alkylthio- and alkoxy-substituted o-quinones towards the biologically relevant thiols, cysteine and glutathione. The o-quinones were generated by rapid (microsecond) one-electron oxidation of the corresponding stable synthesized catechols, forming semiquinones which disproportionated over milliseconds to o-quinones. The latter reacted with the thiols in a pH-dependent manner, indicative of increased nucleophilicity of the thiolate anions as compared with their protonated forms, with rate constants in the region of 10(5)-10(6) M-1s-1. At pH 7.2, within the physiological range, the alkylthio-substituted o-quinones reacted with the thiols approximately 5-10 times faster than the alkoxy-substituted o-quinones. The corresponding alkylthio-substituted phenols might, therefore, in principle, be expected to be more effective targeted anti-melanoma drugs than their alkoxy-substituted counterparts. NMR studies of the reactions of several of the quinones with cysteine indicate that, where addition occurs, the product is exclusively the 6-S-cysteinyl-4-substituted-catechol.
    Citation
    Reactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents. 1992, 2 (5-6):283-93 Melanoma Res.
    Journal
    Melanoma Research
    URI
    http://hdl.handle.net/10541/108938
    PubMed ID
    1337996
    Type
    Article
    Language
    en
    ISSN
    0960-8931
    Collections
    All Paterson Institute for Cancer Research

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