Mechanism of Isomerization of 4-Propyl-o-quinone to Its Tautomeric p-Quinone Methide

Abstract

In previous work, we showed that o-quinones (3,5-cyclohexadiene-1,2-diones) can isomerize to p-quinone methides (4-alkyl-2,5-cyclohexadien-1-one) at rates which depend on the type of substituent at the para position [Iverson, S. L., Hu, L. Q., Vukomanovic, V., and Bolton, J. L. (1995) Chem. Res. Toxicol. 8, 537-544]. In the present investigation, we explored the mechanism of this isomerization reaction using 4-propyl-3,5-cyclohexadiene-1,2-dione (PQ) and its benzyl dideuterio analog 4-(1',1'-dideuteriopropyl)-3,5-cyclohexadiene-1, 2-dione (DPQ). The results show that the isomerization reaction is general base-catalyzed, which suggests that amino acids on proteins with basic side chains could catalyze the reaction in vivo. The Bronsted beta value was determined to be 0.23 +/- 0.02, consistent with the transfer of a proton in the rate-determining step. The rate/pH profile generated from the buffer dilution plots showed dependence on hydroxide ion concentration from pH 7.8 to 9, indicative of base catalysis. From pH 6 to 7.8, the reaction was independent of pH, suggesting that other processes compete at low buffer concentration in this pH region. Substitution of the benzyl CH2 group with CD2 dramatically slows the isomerization reaction. The kinetic deuterium isotope effect on quinone methide formation was determined by measuring the amount of quinone methide trapped as GSH conjugates from PQ compared with DPQ. The isotope effect on product formation was 5.5 +/- 0.6, 37 degrees C. These data provide further evidence that formation of these electrophilic quinone methides from o-quinones could be catalyzed by basic residues in vivo and that the reaction could be inhibited by deuterium substitution at the benzyl methylene group.

Investigation of the regio- and stereo-selectivity of deoxyguanosine linkage to deuterated 2-hydroxyestradiol by using liquid chromatography/ESI-ion trap mass spectrometry

“…This result indicated that an isotope effect may occur in the formation of the p-quinone methides for 1 and 2, in which the hydrogen elimination is favored compared to that of the deuterium atom. A similar isotope effect has also been reported for the isomerization of 4-propyl-o-quinone into its tautomeric pquinone methide form [41] and was in the range of k H /k D ϭ 5.5 Ϯ 0.6 at 37°C.…”

“…In a similar way, the formation of adducts between quinones and glutathione was also shown to involve such isomerization processes [39 -42]. Thus, by analogy with a previously reported basecatalyzed isomerization process [41], a mechanism involving acidic catalysis can be proposed for the formation of covalent adducts between estradiol-2,3-quinone and deoxyguanosine in the acidic medium used in this work (Scheme 2).…”

Studies of para-quinomethane formation during the tyrosinase-catalyzed oxidation of 4-alkylcatechols

“…We oxidized 4-ethylcatechol in (i) CD 3 OH and (ii) CD 3 OH/ CDCl 3 (1:9) solution using one equivalent of 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and monitored the mixture using 1 H NMR. In both cases this rapidly gave a clean spectrum of 4- 23 We next investigated whether the significant amounts of para-quinomethane formed as secondary products during the enzymatic oxidation of 4-alkylcatechols contribute to the inactivation of tyrosinase during catechol oxidation. A solution of 4-methylcatechol (0.4 mM) was oxidised by tyrosinase in a spectrophotometer cuvette until oxygen uptake ceased (15 min).…”

“…These results are entirely in accord with earlier studies by Bolton and co-workers who trapped para-quinomethanes as their glutathione adducts and showed that the ortho-quinone rearrangement is base catalyzed. 22,23 The different .…”

Electrochemical oxidation of substituted catechols in the presence of pyrazol-5-ones: characterization of products and reaction mechanism

“…In addition, the p-benzoquinone methides are much more electrophilic than the o-benzoquinone tautomers and thus nucleophilic addition takes place readily. 37,38 In the cases of 4-methylcatechol (1c) and 3-methylcatechol (1d), the methyl group could also deactivate the 1,6-addition by electronic effects, but such electronic effect (hyperconjugation) is rather weak. Also, the methyl group is less bulky that a tert-butyl group.…”