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

2.50
Hdl Handle:
http://hdl.handle.net/10541/108938
Title:
Reactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents.
Authors:
Cooksey, C J; Jimbow, K; Land, Edward J; Riley, P A
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.
Affiliation:
Department of Chemistry, University College London, UK.
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
Issue Date:
Dec-1992
URI:
http://hdl.handle.net/10541/108938
PubMed ID:
1337996
Type:
Article
Language:
en
ISSN:
0960-8931
Appears in Collections:
All Paterson Institute for Cancer Research

Full metadata record

DC FieldValue Language
dc.contributor.authorCooksey, C Jen
dc.contributor.authorJimbow, Ken
dc.contributor.authorLand, Edward Jen
dc.contributor.authorRiley, P Aen
dc.date.accessioned2010-08-03T11:21:28Z-
dc.date.available2010-08-03T11:21:28Z-
dc.date.issued1992-12-
dc.identifier.citationReactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents. 1992, 2 (5-6):283-93 Melanoma Res.en
dc.identifier.issn0960-8931-
dc.identifier.pmid1337996-
dc.identifier.urihttp://hdl.handle.net/10541/108938-
dc.description.abstractIt 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.en
dc.language.isoenen
dc.subject.meshCell Survival-
dc.subject.meshDrug Design-
dc.subject.meshHumans-
dc.subject.meshIndicators and Reagents-
dc.subject.meshMagnetic Resonance Spectroscopy-
dc.subject.meshMelanoma-
dc.subject.meshMonophenol Monooxygenase-
dc.subject.meshQuinones-
dc.subject.meshSpectrophotometry-
dc.subject.meshStructure-Activity Relationship-
dc.subject.meshSulfhydryl Compounds-
dc.subject.meshSuperoxides-
dc.titleReactivity of orthoquinones involved in tyrosinase-dependent cytotoxicity: differences between alkylthio- and alkoxy-substituents.en
dc.typeArticleen
dc.contributor.departmentDepartment of Chemistry, University College London, UK.en
dc.identifier.journalMelanoma Researchen
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