Synthesis and Tumor-Initiating Activities of Dimethylchrysenes

Shantu Amin, George Balanikas, Keith Huie, Stephen S. Hecht

Research output: Contribution to journalArticle

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Abstract

Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5,7-dimethylchrysene (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.

Original languageEnglish (US)
Pages (from-to)349-355
Number of pages7
JournalChemical Research in Toxicology
Volume1
Issue number6
DOIs
StatePublished - Nov 1 1988

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Tumors
Skin
Neoplasms
Salmonella
Bioassay
Polycyclic Aromatic Hydrocarbons
Epoxy Compounds
Salmonella typhimurium
Structure-Activity Relationship
Biological Assay
Carcinogens
5-methylchrysene
1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene
calf thymus DNA
5,6-dimethylchrysene

All Science Journal Classification (ASJC) codes

  • Toxicology

Cite this

Amin, Shantu ; Balanikas, George ; Huie, Keith ; Hecht, Stephen S. / Synthesis and Tumor-Initiating Activities of Dimethylchrysenes. In: Chemical Research in Toxicology. 1988 ; Vol. 1, No. 6. pp. 349-355.
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abstract = "Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5,7-dimethylchrysene (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.",
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Synthesis and Tumor-Initiating Activities of Dimethylchrysenes. / Amin, Shantu; Balanikas, George; Huie, Keith; Hecht, Stephen S.

In: Chemical Research in Toxicology, Vol. 1, No. 6, 01.11.1988, p. 349-355.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Synthesis and Tumor-Initiating Activities of Dimethylchrysenes

AU - Amin, Shantu

AU - Balanikas, George

AU - Huie, Keith

AU - Hecht, Stephen S.

PY - 1988/11/1

Y1 - 1988/11/1

N2 - Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5,7-dimethylchrysene (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.

AB - Previous studies have shown that 5-methylchrysene (5-MeC) is more carcinogenic on mouse skin than the other methylchrysenes and that the structural requirements favoring tumorigenicity of methylated polynuclear aromatic hydrocarbons are the presence of a bay region methyl group and free peri position, both adjacent to an unsubstituted angular ring. The purpose of this study was to extend these structure-activity relationships to dimethylchrysenes. The following dimethylchrysenes were synthesized: 1,5-dimethylchrysene (1,5-diMeC), 5,6-diMeC, 5,7-diMeC, 5,12-diMeC, 1,6-diMeC, 6,7-diMeC, and 6,12-diMeC. Bioassays of these compounds for tumor-initiating activity on mouse skin demonstrated that all were significantly less tumorigenic than 5-MeC; only 5,6-diMeC had significant tumorigenic activity. Since the relatively low activities of 5,7-diMeC and 5,6-diMeC were unexpected on the basis of the structural requirements stated above, anti-1,2-dihydroxy-3,4-epoxy-l,2,3,4-tetrahydro-5,7-dimethylchrysene (anti-5,7-diMeC-1,2-diol-3,4-epoxide) was synthesized. Its mutagenicity in Salmonella typhimurium and reactivity with calf thymus DNA were compared to those of the major ultimate carcinogen of 5-MeC, anti-5-MeC-1,2-diol-3,4-epoxide. It was strongly mutagenic (2500 revertants/nmol), although less active than anti-5-MeC-1,2-diol-3,4-epoxide (7200 revertants/nmol). Its reactivity with calf thymus DNA was similar to that of anti-5-MeC-1,2-diol-3,4-epoxide. The results of this study demonstrate that the structural requirements which favor tumorigenicity of monomethylchrysenes are not sufficient for high tumorigenicity of dimethylchrysenes.

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