Tyrosinase‐Mediated Cytotoxicity of 4‐Substituted Phenols: Use of QSAR to Forecast Reactivities of Thiols towards the Derived<i>ortho</i>‐Quinones

Abstract

Abstract Certain 4‐substituted phenols can behave as tyrosine analogues and undergo tyrosinase‐catalysed oxidation to cytotoxic o ‐quinones which react with crucial cellular thiols. Such phenols are potential melanogenesis‐specific pro‐drugs for the chemotherapy of malignant melanoma. Previously (Cooksey et al. (1995) Anti‐Cancer Drug Design , 10 , 119), by pulse radiolysis under oxidative conditions of the corresponding stable catechols in the presence and absence of thiols, we showed that the glutathione and cysteine reactivities of ten 4‐substituted o ‐quinones correlated well with the Hammett σ p constants of the corresponding substituents. Starting from the corresponding catechols, one of which has not previously been described, we have now investigated six further 4‐substituted o ‐quinones including two with substituent σ p values higher than those previously studied. Extrapolation of the earlier quantitative structure ‐ activity relationships (QSAR) correctly predicted the high reactivities of these two o ‐quinones, with respective substituents OCF 3 and CH 2 NH 3 + , towards thiols. The data for all sixteen 4‐substituted o ‐quinones, and for o ‐benzoquinone itself, have been combined to provide updated, statistically significant Hammett and Swain‐Lupton correlations, including multivariate regressions using the data for both thiols. These relationships show that in reacting the substituted o ‐quinones with thiols, the rate constants increase with the electron withdrawing capacities of the substituent groups, this being principally due to the resonance effect, with a smaller but significant contribution attributable to the field effect. Such QSAR may facilitate the design of improved melanogenesis ‐ targeted anti‐melanoma prodrugs.