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Catalyzing aromatic hydroxylation

A relatively stable QM is produced by initial P450-catalyzed aromatic hydroxylation of the SERM tamoxifen to yield 4-hydroxytamoxifen, followed by a cytochrome P450-catalyzed direct two-electron oxidation (Scheme 10.9).7 58 This QM is extremely long lived at physiological pH and temperature (tl/2 3 h, Table 10.2),59 most likely... [Pg.344]

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. [Pg.91]

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. [Pg.51]

Mechanism of cytochrome P450-catalyzed aromatic hydroxylation of estrogens. Chem. Res. Toxicol., 10, 767-771. [Pg.195]

A 4fl-hydroperoxy adduct (23) has been observed directly with flavoprotein monooxygenases [111,112]. These enzymes catalyze aromatic hydroxylation however their substrates are phenols rather than an unactivated phenyl ring. They do not... [Pg.384]

Sarabia, S.F., B.T. Zhu, T. Kurosawa, M. Tohma, and J.G. Liehr (1997). Mechanism of cytochrome P450-catalyzed aromatic hydroxylation of estrogens. Chem. Res. Toxicol. 10, 767-771. [Pg.237]

In some cases, quinone-imine formation requires an initial hydroxylation step as illustrated with the nonsteroidal anti-inflammatory drug and idiosyncratic hepatotoxin diclofenac. Thus, CYP-catalyzed aromatic hydroxylation para to the aniline nitrogen affords thepara-hydroxydiclofenac isomers, which can then undergo CYP or peroxidase-mediated oxidation to the quinone-imines amenable to trapping with GSH (Scheme 6) (Tang et al., 1999 Miyamoto et al., 1997). The aniline nitrogen in quinone-imine derivatives can also be part of a heterocyclic... [Pg.51]

Starting from Benzene. In the direct oxidation of benzene [71-43-2] to phenol, formation of hydroquinone and catechol is observed (64). Ways to favor the formation of dihydroxybenzenes have been explored, hence CuCl in aqueous sulfuric acid medium catalyzes the hydroxylation of benzene to phenol (24%) and hydroquinone (8%) (65). The same effect can also be observed with Cu(II)—Cu(0) as a catalytic system (66). Efforts are now directed toward the use of Pd° on a support and Cu in aqueous acid and in the presence of a reducing agent such as CO, H2, or ethylene (67). Aromatic... [Pg.489]

Pure parathion is a pale yellow, practically odorless oil, which crystallizes in long white needles melting at 6.0° C. (17). It is soluble in organic solvents, except kerosenes of low aromatic content, and is only slightly soluble in water (15 to 20 p.p.m. at 20° to 25° C.). Peck (35) measured its rate of hydrolysis to diethyl thiophosphate and nitro-phenate ions in alkaline solutions. He found that the reaction kinetics are first order with respect to the ester and to hydroxyl ion. In normal sulfuric acid the rate of hydrolysis was the same as in distilled water. Peck concluded that hydrolysis takes place by two mechanisms—a reaction catalyzed by hydroxyl ions and an independent uncatalyzed reaction with water. He calculated that at a pH below 10 the time for 50% hydrolysis at 25° C. is 120 days in the presence of saturated lime water the time is 8 hours. The over-all velocity constant at 25° C. is k = 0.047 [OH-] + 4 X 10-6 min.-1... [Pg.153]

Cytochrome P-450. Cytochrome P-450 enzymes consist of a large number of haem-containing mono-oxygenases which catalyze aliphatic and aromatic hydroxylations, epoxidations, as well as other oxidation reactions thus, these enzymes are able to cleave aromatic C-H bonds and also... [Pg.242]

The concept of microbial models of mammalian metabolism was elaborated by Smith and Rosazza for just such a purpose (27-32). In principle, this concept recognizes the fact that microorganisms catalyze the same types of metabolic reactions as do mammals (32), and they accomplish these by using essentially the same type of enzymes (29). Useful biotransformation reactions common to microbial and mammalian systems include all of the known Phase I and Phase II metabolic reactions implied, including aromatic hydroxylation (accompanied by the NIH shift), N- and O-dealkylations, and glucuronide and sulfate conjugations of phenol to name but a few (27-34). All of these reactions have value in studies with the alkaloids. [Pg.340]

Smith and Rosazza have suggested that microbial transformation experiments could best be carried out by using a series of perhaps 10 metabolitically prodigious microorganisms as microbial models. Microorganisms for such work may be selected on the basis of considerable literature precedence for their abilities to catalyze the desired biotransformation reaction (i.e., O-dealkylation, N-dealkylation, aromatic hydroxylation, and reductions). The alkaloid substrate... [Pg.340]

Peroxidases have also been utilized for preparative-scale oxidations of aromatic hydrocarbons. Procedures have been optimized for hydroxylation of l-tyrosine, D-(-)-p-hydroxyphenylglycine, and L-phenylalanine by oxygen, di-hydroxyfumaric acid, and horseradish peroxidase (89). Lactoperoxidase from bovine milk and yeast cytochrome c peroxidase will also catalyze such hydroxylation reactions (89). [Pg.349]

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. [Pg.108]

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. [Pg.108]

Mason and coworkers [44,45] have for the first time observed that HRP catalyzes the hydroxylation of aromatic compounds by molecular oxygen in the pre-... [Pg.87]

Peroxidases have been used very frequently during the last ten years as biocatalysts in asymmetric synthesis. The transformation of a broad spectrum of substrates by these enzymes leads to valuable compounds for the asymmetric synthesis of natural products and biologically active molecules. Peroxidases catalyze regioselective hydroxylation of phenols and halogenation of olefins. Furthermore, they catalyze the epoxidation of olefins and the sulfoxidation of alkyl aryl sulfides in high enantioselectivities, as well as the asymmetric reduction of racemic hydroperoxides. The less selective oxidative coupHng of various phenols and aromatic amines by peroxidases provides a convenient access to dimeric, oligomeric and polymeric products for industrial applications. [Pg.103]

The incorporation of vanadium(V) into the framework positions of silicalite-2 has been reported by Hari Prasad Rao and Ramaswamy . With this heterogeneons oxidation catalyst the aromatic hydroxylation of benzene to phenol and to a mixtnre of hydroqninone and catechol conld be promoted. A heterogeneons ZrS-1 catalyst, which has been prepared by incorporation of zirconinm into a silicalite framework and which catalyzes the aromatic oxidation of benzene to phenol with hydrogen peroxide, is known as well in the literature. However, activity and selectivity were lower than observed with the analogous TS-1 catalyst. [Pg.528]

The triflic acid catalyzed electrophilic hydroxylation of aromatics with BTSP gives the corresponding phenols in high yields without apparent polyhydroxylation or secondary oxidation. Thus, treatment of CeHe with CF3SO3H followed by BTSP gave 11% PhOH. The isomer distributions are in accord with the electrophilic nature of the reaction. The observed ortho/para ratio in the case of toluene agrees with the expected trends (Scheme 4 and Table ll) . [Pg.794]

The NIH shift has been found to occur during aromatic hydroxylations catalyzed by enzymes present in plants, animals, fungi and bacteria. It is thus evident that the acid catalyzed (or spontaneous) isomerization of oxepins-arene oxides is a very important type of in vivo reaction. It should be emphasized that the NIH shift may occur under either acid-catalyzed or neutral (spontaneous) conditions (76ACR378). The direct chemical oxidation of aromatic rings has also yielded both phenols (obtained via the NIH shift) and arene oxides (80JCS(P1)1693>. [Pg.566]

Tamoxifen can undergo several routes of oxidative metabolism (Fig. 7.9). Thus, as expected aromatic hydroxylation to yield, the 4-hydroxy tamoxifen is catalyzed by cytochrome P-450. This metabolite is eliminated after conjugation. Alternatively, oxidation of the alkyl groups attached to the nitrogen atom, also catalyzed by cytochrome P-450, leads to dealkylation (Fig. 7.9). These are detoxication pathways. [Pg.304]

In mammalian liver microsomes, cytochrome P-450 is not specific and catalyzes a wide variety of oxidative transformations, such as (i) aliphatic C—H hydroxylation occurring at the most nucleophilic C—H bonds (tertiary > secondary > primary) (ii) aromatic hydroxylation at the most nucleophilic positions with a characteristic intramolecular migration and retention of substituents of the aromatic ring, called an NIH shift,74 which indicates the intermediate formation of arene oxides (iii) epoxidation of alkenes and (iv) dealkylation (O, N, S) or oxidation (N, S) of heteroatoms. In mammalian liver these processes are of considerable importance in the elimination of xenobiotics and the metabolism of drugs, and also in the transformation of innocuous molecules into toxic or carcinogenic substances.75 77... [Pg.326]


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See also in sourсe #XX -- [ Pg.5 , Pg.456 ]




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