Mechanism of the aromatization of arene oxides

Kasperek, George J.; Bruice, Thomas C.

doi:10.1021/ja00756a035

Cited by 75 publications

(42 citation statements)

References 3 publications

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“…However, most data are consistent with an oxenoid mechanism involving the intermediacy of an arene oxide and the formation of phenolic metabolites via nonenzymatic rearrangement (32). This process is usually accompanied by the so-called NIH shift (27,28,(33)(34)(35) or retention of a substituent a t the site of hydroxylation by rearrangement to an adjacent carbon (Scheme V).…”

Section: Scheme Zvmentioning

confidence: 80%

Microbial Models of Mammalian Metabolism

Smith¹,

Rosazza²

1983

J. Nat. Prod.

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A solid basis for the M4-approach has been developed over the past 10 years. Recent examples of the production of difficult-to-synthesize mammalian metabolites through microbial transformations attest to the utility of the methodology. There is, however, much more to be done. Model studies should be conducted to test parallels between microbial and mammalian S- and N-oxidations, O-glucuronidations, and ester and amide hydrolyses. Subsequently, even greater applications of M4- work can be envisioned. We have been pleased to see our colleagues in industry and academia adopt the M4- approach to solve difficult pharmacological and toxicological problems. In large measure, this has been our greatest reward for efforts initially presented before the membership of the American Society of Pharmacognosy in 1973.

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Section: Scheme Zvmentioning

confidence: 80%

Microbial Models of Mammalian Metabolism

Smith¹,

Rosazza²

1983

J. Nat. Prod.

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Section: Scheme Zvmentioning

confidence: 79%

Microbial Models of Mammalian Metabolism

Smith¹,

Rosazza

1975

Journal of Pharmaceutical Sciences

190

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“…Epoxides are shown to: (1) bind to cellular macromolecules (33), (2) (32), and (4) form dihydrodiols in reactions catalyzed by the microsomal epoxide hydratase (32). Although NIH shift mechanism is shown to be involved in the nonenzymatic rearrangement of epoxides to phenolic derivatives (42)(43)(44), there have been examples of direct enzymatic formation of a phenol (42). In the in vitro metabolism of benzo[a]pyrene (BP), there has been direct evidence for the presence of BP-4,5-oxide (17) and indirect evidence for the presence of BP-7,8-oxide and BP-9,10-oxide (18,30).…”

Section: Discussionmentioning

confidence: 99%

Metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomes.

Yang¹,

Dower²

1975

Proc. Natl. Acad. Sci. U.S.A.

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High pressure liquid chromatography has enabled quantitative analysis of the in vitro metabolism of 7,12-dimethylbenz[a]anthracene, 7-methyl-12-hydroxymethyl-benz [alanthracene, 7-hydroxymethyl-12-methylbenz[alanthracene, and 7,12-dihydroxymethylbenz[a]anthracene by 3-methylcholanthrene-induced and control rat liver microsomes. The following previously unrecognized metabolites have been tentatively identified: 5,-dihydro-5,6-dihydroxy-7-methyl-12-hydroxymethylbenz [alanthracene, 3-hydroxy-7,12-dihydrodihydroxymethylbenz[alanthracene, 4-hydroxy-7,12-dihydrodihydroxymethylbenz[a]anthracene, and 8,9-dihydro-8,9-dihydroxy-7,12-dihydroxymethylbenz[alanthracene.The epoxide hydratase inhibitor 1,2-epoxy-3,3,3-trichloropropane was found to eliminate all dihydrodiol formation and markedly inhibit the formation of several dimethylbenzanthracene metabolites. It is proposed that the tentatively identified 3-hydroxy and 4-hydroxy derivatives are formed by an enzymatic mechanism that does not involve epoxides as intermediates. The metabolic pathways of 7,12-dimethylbenz [a] (4,5), and to be mutagenic in bacteria (6) and mammalian cells (7). The carcinogenic and mutagenic activities of polycyclic aromatic hydrocarbons (PAH) require metabolic activation by mixed-function oxidases located in the microsomes of mammalian cells (7)(8)(9). The enzyme system is present and inducible in Mvo and in cells grown in culture (10-13). PAH are metabolized to phenols, dihydrodiols, quinones, and epoxides (14-23). In DMBA metabolism, the hydroxylation of the 7-methyl group is believed to be the key step towards carcinogenesis in the mammary glands and adrenal necrosis in rats (19,(24)(25)(26). Administration of certain aromatic compounds to rats prior to the feeding of DMBA prevents the induction of adrenal necrosis by this carcinogen and also inhibits the development of mammary cancer (17,27 8,9-dihydroxy-DMBA; presumed to be trans form; 3-OH-DMBA, 3-hydroxy-DMBA; DMBA-phenols, hydroxy derivatives of DMBA; DMBA-5,6-oxide, DMBA-5,6-epoxide; Other derivatives of DMBA, 7-M-12-OHMBA, 7-OHM-12-MBA, and 7,12-diOHMBA, are similarly abbreviated as above; TCPO, 1,2-epoxy-3,3,3-trichloropropane; HPLC, high-pressure liquid chromatography; MC, 3-methylcholanthrene; BP, benzo[ajpyrene; PAH, (30).High-Pressure Liquid Chromatography. A Dupont model 830 high-pressure liquid chromatograph fitted with a 1 m Permaphase octadecyltrimethoxysilane (ODS) column was used. The column was maintained at 50°and 500 pounds/inch2 (3.4 MPa). The column was eluted with a linear gradient of methanol in water from 20% to 80%.Five microliters of prepared metabolite sample in methanol were injected with the solvent flow stopped. The eluent was monitored by ultraviolet absorption at 254 nm. Tendrop fractions were collected (12-19 sec intervals) and the radioactivity was determined. The counting data was converted to pmol by a simple computer program with calibrated counting efficiency. RESULTSIdentification of DMBA Metabolites. DMBA metabolites were identified by th...

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Mechanism of the aromatization of arene oxides

Cited by 75 publications

References 3 publications

Microbial Models of Mammalian Metabolism

Microbial Models of Mammalian Metabolism

Microbial Models of Mammalian Metabolism

Metabolic pathways of 7,12-dimethylbenz[a]anthracene in hepatic microsomes.

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