title: Reactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents.
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.
authors.affiliation: Department of Chemistry, University College London, UK.
authors.forename: C J
authors.initials: CJ
authors.lastname: Cooksey
authors.forename: K
authors.initials: K
authors.lastname: Jimbow
authors.forename: E J
authors.initials: EJ
authors.lastname: Land
authors.forename: P A
authors.initials: PA
authors.lastname: Riley
mesh_terms: D002470:Cell Survival / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D008545:Melanoma / Q000188:drug therapy; D014442:Monophenol Monooxygenase / Q000378:metabolism*; D011809:Quinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013053:Spectrophotometry; D013329:Structure-Activity Relationship; D013438:Sulfhydryl Compounds; D013481:Superoxides
chemical_list: D007202:Indicators and Reagents; D011809:Quinones; D013438:Sulfhydryl Compounds; D013481:Superoxides; D014442:Monophenol Monooxygenase