Aromatic hydroxylation mechanism

Reinhold and Bruni studied the metabolism of 7,9-dideuterioellipticine (17) in rats and found that deuterium originally at position 9 was completely lost during the mammalian hydroxylation process (147). Proton and carbon-13 NMR and mass spectral analyses confirmed the complete elimination of deuterium at position 9, thus ruling out the occurrence of an NIH shift mechanism in the hydroxylation of ellipticine. An oxygen-insertion process was rationalized to account for the mechanism of aromatic hydroxylation in rats since this would not be expected to display the NIH shift but should demonstrate an isotope effect. It was... 

That cytochrome P450-catalyzed aromatic hydroxylation proceeded by a mechanistic pathway that was generally consistent with the rules of electrophilic aromatic substitution was never in doubt because of the abundance of experimental evidence supporting this conclusion. Despite the certainty of product formation, establishing the exact mechanism that defines the pathway has proved to be difficult. 

Bush ED, Trager WF. Substrate probes for the mechanism of aromatic hydroxylation catalyzed by cytochrome P-450 selectively deuterated analogues of warfarin. J Med Chem 1985 28(8) 992-996. 

Darbyshire JF, Iyer KR, Grogan J, et al. Substrate probe for the mechanism of aromatic hydroxylation catalyzed by cytochrome P450. Drug Metab Dispos 1996 24(9) 1038-1045. 

Aromatic hydroxylation may also take place by a mechanism other than epoxidation. Thus, the ra-hydroxylation of chlorobenzene is thought to proceed via a direct insertion mechanism (Fig. 4.7). 

An attempt was made to reveal the mechanism for the formation of free radicals upon irradiation of titanium dioxide in the presence of benzene and toluene. Careful examination of the effects of oxygen and water showed that the presence of oxygen is essential for the reaction, and that under oxygen the oxidation of water contributes to the aromatic hydroxylation and the oxidation of toluene as a substrate leads to oxidation of its side chain (56). 

Breslin DT, Schuster GB (1996) Anthraquinone photonucleases mechanisms for GG-selective and nonselective cleavage of double-stranded DNA. J Am Chem Soc 118 2311-2319 BrodieBB, Axelrod J, Shore PA, Udenfriend S (1954) Ascorbic acid in aromatic hydroxylation. II. Products formed by reaction of substrates with ascorbic acid, ferrous ion, and oxygen. J Biol Chem 208 741-750... 

Viehe HG, Janousek Z, Merenyi R, Stella L (1985) The captodative effect. Acc Chem Res 18 148-154 Volkert O, Schulte-Frohlinde D (1968) Mechanism of homolytic aromatic hydroxylation III. Tetrahedron Lett 2151-2154... 

Valgimigli L, Banks JT, Ingold Kl, Lusztyk J (1995) Kinetic solvent effects on hydroxylic hydrogen atom abstractions are independent of the nature of the abstracting radical. Two extreme tests using Vitamin Eand phenol. J Am Chem Soc 117 9966-9971 Viehe HG, Janousek Z, Merenyi R, Stella L (1985) The captodative effect. Acc Chem Res 18 148-154 Volkert 0, Schulte-Frohlinde D (1968) Mechanism of homolytic aromatic hydroxylation III. Tetrahedron Lett 2151-2154... 

Korzekwa KR, Swinney DC, Trager WF. Isotopically labeled chlorobenzenes as probes for the mechanism of cytochrome P-450 catalyzed aromatic hydroxylation. Biochemistry 1989 28(23) 9019-9027. 

Ridder, L., Mulholland, A.J., Rietjens, I.M.C.M., and Vervoort J., Combined quantum mechanical and molecular mechanical reaction pathway calculation for aromatic hydroxylation by p-hydroxybenzoate-3-hydroxylase, J. Mol. Graphics Modeling, 17, 163-175, 1999. 

Bathelt CM, L Ridder, AJ Mulholland, JN Harvey (2003) Aromatic hydroxylation by cytochrome P450 Model calculations of mechanism and substituent effects. J. Am. Chem. Soc. 125 (49) 15004-15005... 

Although regulation is unique for each member of the aromatic amino acid hydroxylase family, the catalytic mechanism and cofactor requirements for members of the family are identical. During the reactions of all three enzymes, the dioxygen molecule is cleaved and incorporated as a hydroxyl group into both the aromatic amino acid and BH4. Each enzyme in the family displays its own unique substrate specificity profile. Two interesting questions about this enzyme family relate to the actual hydroxylation mechanism and how enzyme activity is altered by changes in BH4 levels. Problems in any one of these hydroxylation systems can arise from either an inadequate supply of the BH4 cofactor or a defect in the enzyme or its expression. 

The Phase II acetylation of aromatic hydroxyl-amineS/ the products of Phase I metabolism of aromatic amineS/ constitutes a toxic metabolic pathway that has been implicated in carcinogenesis/ as illustrated in Scheme 11.36. Rapid acetylators (with respect to NAT2) have been shown to be associated with an increased risk of colon cancer. The mechanism of this toxicity has implicated the intermediacy of the reactive... 

The oxidation of m-cresol was carried out in Parr autoclave at 353 K using a 3 1 mixture of H2O and acetonitrile as solvent and Sn-silicalites with Si/Sn ratio of 70 as catalysts. A slightly higher efficiency for H2O2 is seen with Sn-ZSM-12 sample (Table 4). The dihydroxylated products, viz., 2-methylhydroquinone and 4-methylcatechol are found to be in excess over the products of side chain oxidation, viz., 3-hydroxybenzyl alcohol and the aldehyde in the product mkture. The aromatic hydroxylation on Sn-silicalites may follow an ionic mechanism as both the -CH3 and -OH groups in m-cresol are favourably placed for electrophilic substitution reaction. Interestingly, the product distribution on all the three Sn-molecular sieves is almost similar. This shows that in all the three types, the Sn ions are dispersed uniformly and possess identical catalytic property due to similar environment around them. 

Research on aromatic hydroxylation by cytochrome P450 provides an example of how quantum chemical calculations on small models can help in developing structure-reactivity relationships. Hydroxylation of C-H bonds is a particularly important class of reaction in drug metabolism,185 which can activate pro-drugs, or affect the bioavailability of pharmaceuticals. For the reliable prediction of pharmaceutical metabolism and toxicology (ADME/ TOX) properties, a key aim is the development of structure-activity relationships to predict conversions of drugs. Earlier work has shown that structure-activity relationships based on the structures and properties of substrates alone are of limited utility. There is a need for more detailed models, which can include effects of the reaction mechanism and specificity of different cytochrome P450 isozymes. 

Fig. 4.81. Schematic presentation of the reaction mechanism of aromatic hydroxylation by a...

Bathelt CM, Ridder L, Mulholland AJ, Harvey JN. Mechanism and structure-reactivity relationships for aromatic hydroxylation by cytochrome P450. Org Biomol Chem 2004 2 2998-3005. 

Q5.1 The primary metabolic step involves a different mechanism for each of the drugs listed in Figure 5.11. Select the appropriate transformation for each drug from the following list aliphatic hydroxylation, oxidative N-dealkylation, hydrolysis, aromatic hydroxylation, oxidative O-dealkylation. Draw the structure of the primary metabolite in each case. 

Treiber, A., Dansette, R. M., Mansuy, D. Mechanism of the aromatic hydroxylation of thiophene by acid-catalyzed peracid oxidation. J. Org. Chem. 2002, 67, 7261-7266. 

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