Synthesis of Potentially Carcinogenic Higher Oxidized Metabolites of Dibenz[<i>a,j</i>]anthracene and Benzo[<i>c</i>]chrysene

Harvey, Ronald G.; Dai, Wei; Zhang, Jintao; Cortez, Cecilia

doi:10.1021/jo980415r

Cited by 11 publications

(10 citation statements)

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“…Amin [ 39 ] experienced low yields and further oxidation of the bromo-group into quinones while trying to force the reaction away from benzo[c]phenanthrene and towards benzo[a]anthracene. Harvey tested different blocking groups and concluded that the chloro-group works better [ 40 ]. There is still a price to pay for working against the natural pathway as illustrated in Scheme 13 .…”

Section: Controlling Product Formation With Blocking Groupsmentioning

confidence: 99%

Photochemical Oxidative Cyclisation of Stilbenes and Stilbenoids—The Mallory-Reaction

2010

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After Mallory described in 1964 the use of iodine as catalyst for the photochemical cyclisation of stilbenes, this reaction has proven its effectiveness in the synthesis of phenanthrenes, other PAHs and phenacenes with a surprisingly large selection of substituents. The “early age” of the reaction was reviewed by Mallory in 1984in a huge chapter in the Organic Reactions series, but the development has continued. Alternative conditions accommodate more sensitive substituents, and isomers can be favoured by sacrificial substituents. Herein the further developments and applications of this reaction after 1984 are discussed and summarized.

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Section: Controlling Product Formation With Blocking Groupsmentioning

confidence: 99%

Photochemical Oxidative Cyclisation of Stilbenes and Stilbenoids—The Mallory-Reaction

2010

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“…Photocyclization of 15 in the presence of I 2 and epoxybutane took place with partial displacement of the choro protecting group to furnish 7-chloro-3,4,10-trimethoxydibenz[ a , j ]anthracene ( 16a ) (42% based on conversion of 15 ) and 1,9,10-trimethoxybenzo[ c ]chrysene ( 17 ) (35%) as the principal products. The 1 H NMR spectrum of the former ressembled that of 7-chloro-3,4,11-trimethoxydibenz[ a , j ]anthracene, exhibiting a characteristic singlet at low field (δ 9.77) which is assigned to the sterically crowded meso region H 12 proton. The 1 H NMR spectrum of 17 ressembled that of the closely related 1,2,9,10-tetramethoxybenzo[ c ]chrysene whose synthesis was described in the preceding paper, exhibiting characteristic low-field doublets at δ 8.98 and 8.82 assigned to the H 12 and H 13 protons, respectively, in the sterically crowded fjord region of the benzo[ c ]chrysene ring system.…”

Section: Resultsmentioning

confidence: 96%

“…We now report the syntheses of the unsymmetrical 3,4,8,9-bis(dihydrodiol) 1 and the 10- and 11-phenolic trans -3,4- dihydrodiols ( 3a , b ) of dibenz[ a , j ]anthracene. The stereochemistry of the dihydrodiol functions in all these compounds is trans, since it is well established that metabolism of PAHs by mammalian enzymes furnishes exclusively trans stereoisomers. , The preceding paper reported the syntheses of the terminal ring symmetrical 3,4,10,11-bis(dihydrodiol) of dibenz[ a , j ]anthracene ( 2 ) along with several additional suspected more highly oxidized metabolites of this hydrocarbon …”

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confidence: 99%

Synthesis of Higher Oxidized Metabolites of Dibenz[a,j]anthracene Implicated in the Mechanism of Carcinogenesis

1998

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Higher oxidized metabolites are implicated as active carcinogenic forms of polycyclic aromatic hydrocarbons which have two or more bay or fjord molecular regions, such as dibenz[a,j]anthracene. These include the bis(dihydrodiols) and phenolic dihydrodiols which may potentially undergo further metabolism to the corresponding diol epoxides. The latter react with DNA resulting in mutations that lead to tumorigenesis. Prior characterization of these metabolites has been based largely on HPLC and spectroscopic evidence. This paper reports efficient syntheses of the trans-trans-3,4,8,9-dihydrodiol (1) and the 10- and 11-phenolic trans-3,4-dihydrodiols of dibenz[a,j]anthracene (3a,b). The synthetic route to 1 entails as the key steps asymmetric dihydroxylation of an appropriately substituted stilbene precursor employing a Sharpless catalyst followed by intramolecular cyclodehydrobromination catalyzed by Pd(PPh3)2Cl2. The syntheses of 3a,b proceed via sequences involving a Wittig reaction of anisaldehyde with a phosphonium salt of 2-chloro-3-methylbenzyl bromide to give a stilbene compound and then photocyclization, conversion of the product to a phosphonium salt, a second Wittig reaction and photocyclization, reductive dechlorination, and conversion of the resulting trimethoxydibenz[a,j]anthracenes to the phenolic dihydrodiols. A key feature of these syntheses is the effective use of chloro substituents to block photocyclization in an undesired direction. These methods are potentially applicable to the synthesis of analogous higher oxidized metabolites of other polycyclic aromatic carcinogens.

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“…DB[ a , j ]A- trans -5,6-diol (Chart , X ) and DB[ a , j ]A-5,6-oxide ( IX ) were synthesized as previously described ( , ). Syntheses of DB[ a , j ]A-3,4-10,11-bis-diol ( III ), DB[ a , j ]A-3,4-8,9-bis-diol ( IV ), 10-OH-DB[ a , j ]A-3,4-diol ( VII ), and 11-OH-DB[ a , j ]A-3,4-diol ( VIII ) have been published ( , ). RNase A (EC 3.1.4.22) was obtained from Worthington Biochemical Co. (Freehold, NJ), and micrococcal nuclease ( Staphylococcus aureus , EC 3.1.4.1), apyrase, calf spleen phosphodiesterase (EC 3.1.16.1), and 3‘-phosphatase-free T4 polynucleotide kinase (PNK) (EC 2.7.1.78) were purchased from Boehringer Mannheim Biochemicals (Indianapolis, IN).…”

Section: Methodsmentioning

confidence: 99%

Analysis of Highly Polar DNA Adducts Formed in SENCAR Mouse Epidermis Following Topical Application of Dibenz[a,j]anthracene

Vulimiri

Baer‐Dubowska

Harvey

et al. 1998

Chem. Res. Toxicol.

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The formation of DNA adducts in mouse epidermis has been examined following topical application of dibenz[a,j]anthracene (DB[a,j]A) and its metabolites, i.e., DB[a,j]A-3,4-diol, DB[a,j]A-3,4-10, 11-bis-diol, DB[a,j]A-3,4-8,9-bis-diol, 10-OH-DB[a,j]A-3,4-diol, or 11-OH-DB[a,j]A-3,4-diol, using a 32P-postlabeling assay. At initiating doses (400-1600 nmol), DB[a,j]A produced at least 23 DNA adduct spots, including four less polar (derived from the bay-region syn- and anti-diol-epoxides) and 19 highly polar DNA adducts. DB[a, j]A-3,4-diol produced 13 DNA adduct spots, four less polar and nine highly polar DNA adducts, and DB[a,j]A-3,4-10,11-bis-diol produced nine highly polar DNA adducts. Eight and seven of the highly polar DNA adducts generated by DB[a,j]A-3,4-diol and DB[a,j]A-3,4-10, 11-bis-diol, respectively, migrated in the chromatography system like the highly polar DNA adducts produced by the parent compound. Sufficient amounts of radioactivity were associated with highly polar adduct spots 11, 13, and 22 to confirm their chromatogaphic identity in DNA samples from DB[a,j]A-, DB[a,j]A-3,4-diol-, and DB[a, j]A-3,4-10,11-bis-diol-treated mice. 10-OH-DB[a,j]A-3,4-diol and 11-OH-DB[a,j]A-3,4-diol did not produce any highly polar DNA adducts that could be detected under our experimental conditions. At an initiating dose of 400 nmol, DB[a,j]A, DB[a,j]A-3,4-diol, and DB[a, j]A-3,4-10,11-bis-diol produced 22.4 +/- 13.0, 15.6 +/- 10.1, and 5. 5 +/- 0.3 (mean +/- SD) adducts/10(9) nucleotides, of which 77, 65, and 100%, respectively, represented highly polar DNA adducts. At the same dose of 400 nmol per mouse, DB[a,j]A and its 3,4-diol were able to initiate papillomas in SENCAR mouse skin (3.08 +/- 1.89 and 3.48 +/- 2.72 papillomas per mouse, respectively, after 16 weeks of promotion with 12-O-tetradecanoyl phorbol 13-acetate), while the 3, 4-10,11-bis-diol of DB[a,j]A was inactive as a tumor initiator. A quantitative correlation (r = 0.935; p = 0.0196) between levels of less polar DNA adducts and tumor-initiating activity of DB[a,j]A, DB[a,j]A-3,4-diol, and anti-DB[a,j]ADE was observed. This study demonstrates that the highly polar DNA adducts formed from DB[a,j]A in mouse epidermis arise primarily from the DB[a,j]A-3,4-10, 11-bis-diol. However, the contribution of this metabolite to the tumor-initiating activity of DB[a,j]A appears to be small.

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Synthesis of Potentially Carcinogenic Higher Oxidized Metabolites of Dibenz[a,j]anthracene and Benzo[c]chrysene

Cited by 11 publications

References 20 publications

Photochemical Oxidative Cyclisation of Stilbenes and Stilbenoids—The Mallory-Reaction

Photochemical Oxidative Cyclisation of Stilbenes and Stilbenoids—The Mallory-Reaction

Synthesis of Higher Oxidized Metabolites of Dibenz[a,j]anthracene Implicated in the Mechanism of Carcinogenesis

Analysis of Highly Polar DNA Adducts Formed in SENCAR Mouse Epidermis Following Topical Application of Dibenz[a,j]anthracene

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