Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides

H. S. Gill, P. L. Kole, J. C. Wiley, K. M. Li, S. Higginbotham, Eleanor G Rogan, Ercole Cavalieri

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Abstract

Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycycic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mech anisms of activation, (±)-trans-DB [a,l]P-11,12-dihydrodiol,(±)-anti-DB[a,l]PDE and (±)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclizatlon of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiol epoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 133 nmol of compound In 100 μl of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol In 100 μl acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3,7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodlol and show that the two diolepoxides are less tumorlgenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.

Original languageEnglish (US)
Pages (from-to)2455-2460
Number of pages6
JournalCarcinogenesis
Volume15
Issue number11
DOIs
StatePublished - Nov 1 1994

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Estuaries
Skin
Neoplasms
Acetone
Inbred SENCAR Mouse
Aromatic Hydrocarbons
Epoxy Compounds
Tetradecanoylphorbol Acetate
Carcinogens
dibenzo(a,l)pyrene
dibenzo(a,l)pyrene 11,12-dihydrodiol

ASJC Scopus subject areas

  • Cancer Research

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Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides. / Gill, H. S.; Kole, P. L.; Wiley, J. C.; Li, K. M.; Higginbotham, S.; Rogan, Eleanor G; Cavalieri, Ercole.

In: Carcinogenesis, Vol. 15, No. 11, 01.11.1994, p. 2455-2460.

Research output: Contribution to journalArticle

Gill, H. S. ; Kole, P. L. ; Wiley, J. C. ; Li, K. M. ; Higginbotham, S. ; Rogan, Eleanor G ; Cavalieri, Ercole. / Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides. In: Carcinogenesis. 1994 ; Vol. 15, No. 11. pp. 2455-2460.
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abstract = "Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycycic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mech anisms of activation, (±)-trans-DB [a,l]P-11,12-dihydrodiol,(±)-anti-DB[a,l]PDE and (±)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclizatlon of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiol epoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 133 nmol of compound In 100 μl of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol In 100 μl acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3,7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodlol and show that the two diolepoxides are less tumorlgenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.",
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T1 - Synthesis and tumor-initiating activity in mouse skin of dibenzo[a,l]pyrene syn- and anti-fjord-region diolepoxides

AU - Gill, H. S.

AU - Kole, P. L.

AU - Wiley, J. C.

AU - Li, K. M.

AU - Higginbotham, S.

AU - Rogan, Eleanor G

AU - Cavalieri, Ercole

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N2 - Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycycic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mech anisms of activation, (±)-trans-DB [a,l]P-11,12-dihydrodiol,(±)-anti-DB[a,l]PDE and (±)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclizatlon of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiol epoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 133 nmol of compound In 100 μl of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol In 100 μl acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3,7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodlol and show that the two diolepoxides are less tumorlgenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.

AB - Dibenzo[a,l]pyrene (DB[a,l]P) is the most potent carcinogen among polycycic aromatic hydrocarbons. Because the fjord-region diolepoxide (DE) pathway is one of the mech anisms of activation, (±)-trans-DB [a,l]P-11,12-dihydrodiol,(±)-anti-DB[a,l]PDE and (±)-syn-DB[a,l]PDE were synthesized. The key intermediate for these syntheses, 12-methoxy-DB[a,l]P, was successfully obtained by cyclizatlon of 6-(3-methoxybenzyl)benzanthrone with methanesulfonic acid, which in turn was prepared by 1,4 conjugate addition of 3-methoxybenzyl magnesium bromide to benzanthrone. The presence of the DB[a,l]P nucleus in the dihydrodiol epoxides and diolepoxides was proven by conversion of 12-methoxyDB[a,l]P into the parent compound in several steps. The tumor-initiating activity of the two diolepoxides in mouse skin was compared to that of DB[a,l]P-11,12-dihydrodiol and the parent DB[a,l]P Groups of 24 8 week old female SENCAR mice were topically initiated with 12, 4 or 133 nmol of compound In 100 μl of acetone. Starting 1 week later, promotion with 12-O-tetradecanoylphorbol-13-acetate (1.62 nmol In 100 μl acetone) was begun and continued twice weekly for 30 weeks. At the 12, 4 and 1.33 nmol doses, anti-DB[a,l]PDE induced 2.0, 0.7 and 0.7 tumors per mouse (t/m) respectively, whereas syn DB[a,l]PDE induced 1.8, 1.5 and 1.8 t/m. At the same three doses, DB[a,l]P-11,12-dihydrodiol induced 4.6, 4.3 and 2.8 t/m, and DB[a,l]P resulted in 9.3,7.1 and 5.2 t/m. These results confirm that DB[a,l]P is more potent than its 11,12-dihydrodlol and show that the two diolepoxides are less tumorlgenic than their precursors. At the medium and low doses, syn-DB[a,l]PDE is more tumorigenic than its congener anti-DB[a,l]PDE.

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