Convenient syntheses of dibenzo[c,p]chrysene and its possible proximate and ultimate carcinogens: In vitro metabolism and DNA adduction studies

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Abstract

Dibenzo[c,p]chrysene (DB[c,p]C) is the only hexacyclic polycyclic aromatic hydrocarbon having two Cord regions, both in different chemical environments. Its environmental presence and relative tumorigenic potency are not known due to the lack of synthetic standards. We report here the synthesis of dibenzo[c,p]chrysene (1), its proximate carcinogens, i.e., trans-1,2-dihydroxy- 1,2-dihydro-DB[c,p]C (2) and trans-11,12-dihydroxy-11,12-dihydro-DB[c,p]C (3), and possible ultimate carcinogens, i.e., anti-trans-1,2-dihydroxy-3,4-epoxy-1,2, 3,4-tetrahydro-DB[c,p]C (4) and anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13, 14-tetrahydro-DB[c,p]C (5). The syntheses of 1 and the appropriately methoxy-substituted DB[c,p]C (12 and 27), key intermediates for the synthesis of its proximate and ultimate metabolites, were tried first using a Suzuki cross-coupling reaction. However, the cyclization of olefins (10 and 11) gave poor yields of the desired products. An alternate method was thus developed employing a photochemical approach. The in vitro metabolism of DB[c,p]C was established with the S9 fraction of liver homogenate from phenobarbital/β- naphthoflavone-induced Sprague-Dawley rats. The major dihydrodiol formed was identified as the fjord region 11,12-dihydroxy-11,12-dihydro-DB[c,p]C, while the major and minor phenols were identified as 11-hydroxy-DB[c,p]C and 12-hydroxy-DB[c,p]C, respectively. Further, the DNA adduction studies with the calf thymus DNA led to a mixture of dA and dG adducts for both fjord region diol epoxides (4 and 5). Interestingly, the dA to dG ratio for 1,2-dihydroxy-3,4- epoxide was much higher (3.2) compared to that of 11,12-dihydroxy-13,14-epoxide (0.5).

Original languageEnglish (US)
Pages (from-to)4962-4970
Number of pages9
JournalJournal of Organic Chemistry
Volume70
Issue number13
DOIs
StatePublished - Jun 24 2005

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Metabolism
Carcinogens
DNA
Epoxy Compounds
dibenzo(c,p)chrysene
Phenols
Cyclization
Polycyclic Aromatic Hydrocarbons
Alkenes
Phenobarbital
Metabolites
Liver
Rats

All Science Journal Classification (ASJC) codes

  • Organic Chemistry

Cite this

@article{d730324bcf6c45719f0d35520a1c43ba,
title = "Convenient syntheses of dibenzo[c,p]chrysene and its possible proximate and ultimate carcinogens: In vitro metabolism and DNA adduction studies",
abstract = "Dibenzo[c,p]chrysene (DB[c,p]C) is the only hexacyclic polycyclic aromatic hydrocarbon having two Cord regions, both in different chemical environments. Its environmental presence and relative tumorigenic potency are not known due to the lack of synthetic standards. We report here the synthesis of dibenzo[c,p]chrysene (1), its proximate carcinogens, i.e., trans-1,2-dihydroxy- 1,2-dihydro-DB[c,p]C (2) and trans-11,12-dihydroxy-11,12-dihydro-DB[c,p]C (3), and possible ultimate carcinogens, i.e., anti-trans-1,2-dihydroxy-3,4-epoxy-1,2, 3,4-tetrahydro-DB[c,p]C (4) and anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13, 14-tetrahydro-DB[c,p]C (5). The syntheses of 1 and the appropriately methoxy-substituted DB[c,p]C (12 and 27), key intermediates for the synthesis of its proximate and ultimate metabolites, were tried first using a Suzuki cross-coupling reaction. However, the cyclization of olefins (10 and 11) gave poor yields of the desired products. An alternate method was thus developed employing a photochemical approach. The in vitro metabolism of DB[c,p]C was established with the S9 fraction of liver homogenate from phenobarbital/β- naphthoflavone-induced Sprague-Dawley rats. The major dihydrodiol formed was identified as the fjord region 11,12-dihydroxy-11,12-dihydro-DB[c,p]C, while the major and minor phenols were identified as 11-hydroxy-DB[c,p]C and 12-hydroxy-DB[c,p]C, respectively. Further, the DNA adduction studies with the calf thymus DNA led to a mixture of dA and dG adducts for both fjord region diol epoxides (4 and 5). Interestingly, the dA to dG ratio for 1,2-dihydroxy-3,4- epoxide was much higher (3.2) compared to that of 11,12-dihydroxy-13,14-epoxide (0.5).",
author = "Arun Sharma and Lin, {Jyh ming} and Dhimant Desai and Shantu Amin",
year = "2005",
month = "6",
day = "24",
doi = "10.1021/jo040291k",
language = "English (US)",
volume = "70",
pages = "4962--4970",
journal = "Journal of Organic Chemistry",
issn = "0022-3263",
publisher = "American Chemical Society",
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TY - JOUR

T1 - Convenient syntheses of dibenzo[c,p]chrysene and its possible proximate and ultimate carcinogens

T2 - In vitro metabolism and DNA adduction studies

AU - Sharma, Arun

AU - Lin, Jyh ming

AU - Desai, Dhimant

AU - Amin, Shantu

PY - 2005/6/24

Y1 - 2005/6/24

N2 - Dibenzo[c,p]chrysene (DB[c,p]C) is the only hexacyclic polycyclic aromatic hydrocarbon having two Cord regions, both in different chemical environments. Its environmental presence and relative tumorigenic potency are not known due to the lack of synthetic standards. We report here the synthesis of dibenzo[c,p]chrysene (1), its proximate carcinogens, i.e., trans-1,2-dihydroxy- 1,2-dihydro-DB[c,p]C (2) and trans-11,12-dihydroxy-11,12-dihydro-DB[c,p]C (3), and possible ultimate carcinogens, i.e., anti-trans-1,2-dihydroxy-3,4-epoxy-1,2, 3,4-tetrahydro-DB[c,p]C (4) and anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13, 14-tetrahydro-DB[c,p]C (5). The syntheses of 1 and the appropriately methoxy-substituted DB[c,p]C (12 and 27), key intermediates for the synthesis of its proximate and ultimate metabolites, were tried first using a Suzuki cross-coupling reaction. However, the cyclization of olefins (10 and 11) gave poor yields of the desired products. An alternate method was thus developed employing a photochemical approach. The in vitro metabolism of DB[c,p]C was established with the S9 fraction of liver homogenate from phenobarbital/β- naphthoflavone-induced Sprague-Dawley rats. The major dihydrodiol formed was identified as the fjord region 11,12-dihydroxy-11,12-dihydro-DB[c,p]C, while the major and minor phenols were identified as 11-hydroxy-DB[c,p]C and 12-hydroxy-DB[c,p]C, respectively. Further, the DNA adduction studies with the calf thymus DNA led to a mixture of dA and dG adducts for both fjord region diol epoxides (4 and 5). Interestingly, the dA to dG ratio for 1,2-dihydroxy-3,4- epoxide was much higher (3.2) compared to that of 11,12-dihydroxy-13,14-epoxide (0.5).

AB - Dibenzo[c,p]chrysene (DB[c,p]C) is the only hexacyclic polycyclic aromatic hydrocarbon having two Cord regions, both in different chemical environments. Its environmental presence and relative tumorigenic potency are not known due to the lack of synthetic standards. We report here the synthesis of dibenzo[c,p]chrysene (1), its proximate carcinogens, i.e., trans-1,2-dihydroxy- 1,2-dihydro-DB[c,p]C (2) and trans-11,12-dihydroxy-11,12-dihydro-DB[c,p]C (3), and possible ultimate carcinogens, i.e., anti-trans-1,2-dihydroxy-3,4-epoxy-1,2, 3,4-tetrahydro-DB[c,p]C (4) and anti-trans-11,12-dihydroxy-13,14-epoxy-11,12,13, 14-tetrahydro-DB[c,p]C (5). The syntheses of 1 and the appropriately methoxy-substituted DB[c,p]C (12 and 27), key intermediates for the synthesis of its proximate and ultimate metabolites, were tried first using a Suzuki cross-coupling reaction. However, the cyclization of olefins (10 and 11) gave poor yields of the desired products. An alternate method was thus developed employing a photochemical approach. The in vitro metabolism of DB[c,p]C was established with the S9 fraction of liver homogenate from phenobarbital/β- naphthoflavone-induced Sprague-Dawley rats. The major dihydrodiol formed was identified as the fjord region 11,12-dihydroxy-11,12-dihydro-DB[c,p]C, while the major and minor phenols were identified as 11-hydroxy-DB[c,p]C and 12-hydroxy-DB[c,p]C, respectively. Further, the DNA adduction studies with the calf thymus DNA led to a mixture of dA and dG adducts for both fjord region diol epoxides (4 and 5). Interestingly, the dA to dG ratio for 1,2-dihydroxy-3,4- epoxide was much higher (3.2) compared to that of 11,12-dihydroxy-13,14-epoxide (0.5).

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