Differences in conformations of covalent adducts derived from the binding of 5- and 6-methylchrysene diol epoxide stereoisomers to DNA

Nicholas Geacintov, Mi Soon Lee, Victor Ibanez, Shantu Amin, Stephen S. Hecht

Research output: Contribution to journalArticle

Abstract

The conformations of adducts derived from the covalent binding of four different isomeric diol epoxide derivatives of 5- or 6-methylchrysene to native double-stranded calf thymus DNA were studied by linear dichroism techniques. Out of four isomers investigated here, only the R,S,S,R enantiomer of anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methyl chrysene, (+)-5-MeCDE, is highly tumorigenic and mutagenic toward Salmonella typhimurium TA100; the S,R,R,S enantiomer, (-)-5-MeCDE, and the corresponding R,S,S,R and S,R,R,S enantiomers of anti-1,2,-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene are non-tumorigenic and much less mutagenic than (+)-5-MeCDE. [Melikian et al., (1988) Cancer Res., 48, 1781 -1787] Only the DNA adducts derived from the binding of (+)-5-MeCDE are characterized by a pronounced positive linear dichroism signal at 308 nm due to the phenanthrenyl residue which is tilted at an angle of 45-48° with respect to the average orientations of the axes of unoriented DNA segments. The phenanthrenyl residues derived from the covalent binding to DNA of the other three inactive or less active isomers appear to be unoriented. The defined orientation of the covalently bound phenanthrenyl residues derived from (+)-5-MeCDE corresponds to adduct conformations which are similar to those obtained from the binding of the highly tumorigenic trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene stereoisomer and other highly active bay-region diol epoxide derivatives to DNA. These findings provide further evidence that there is a correlation between DNA adduct conformation and biological activities for these series of polycyclic aromatic diol epoxide derivatives with R,S,S,R absolute configuration and which are known to bind predominantly to N2 of guanine.

Original languageEnglish (US)
Pages (from-to)985-989
Number of pages5
JournalCarcinogenesis
Volume11
Issue number6
StatePublished - Jun 1990

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Stereoisomerism
Epoxy Compounds
Conformation
Enantiomers
Conformations
Epoxy
DNA
Dichroism
Derivatives
Derivative
Isomers
DNA Adducts
Thymus
Salmonella
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide
Pyrene
Nucleic Acid Conformation
Bioactivity
Guanine
Salmonella typhimurium

ASJC Scopus subject areas

  • Cancer Research
  • Statistics, Probability and Uncertainty
  • Applied Mathematics
  • Physiology (medical)
  • Physiology
  • Behavioral Neuroscience

Cite this

Differences in conformations of covalent adducts derived from the binding of 5- and 6-methylchrysene diol epoxide stereoisomers to DNA. / Geacintov, Nicholas; Lee, Mi Soon; Ibanez, Victor; Amin, Shantu; Hecht, Stephen S.

In: Carcinogenesis, Vol. 11, No. 6, 06.1990, p. 985-989.

Research output: Contribution to journalArticle

Geacintov, Nicholas ; Lee, Mi Soon ; Ibanez, Victor ; Amin, Shantu ; Hecht, Stephen S. / Differences in conformations of covalent adducts derived from the binding of 5- and 6-methylchrysene diol epoxide stereoisomers to DNA. In: Carcinogenesis. 1990 ; Vol. 11, No. 6. pp. 985-989.
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abstract = "The conformations of adducts derived from the covalent binding of four different isomeric diol epoxide derivatives of 5- or 6-methylchrysene to native double-stranded calf thymus DNA were studied by linear dichroism techniques. Out of four isomers investigated here, only the R,S,S,R enantiomer of anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methyl chrysene, (+)-5-MeCDE, is highly tumorigenic and mutagenic toward Salmonella typhimurium TA100; the S,R,R,S enantiomer, (-)-5-MeCDE, and the corresponding R,S,S,R and S,R,R,S enantiomers of anti-1,2,-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene are non-tumorigenic and much less mutagenic than (+)-5-MeCDE. [Melikian et al., (1988) Cancer Res., 48, 1781 -1787] Only the DNA adducts derived from the binding of (+)-5-MeCDE are characterized by a pronounced positive linear dichroism signal at 308 nm due to the phenanthrenyl residue which is tilted at an angle of 45-48° with respect to the average orientations of the axes of unoriented DNA segments. The phenanthrenyl residues derived from the covalent binding to DNA of the other three inactive or less active isomers appear to be unoriented. The defined orientation of the covalently bound phenanthrenyl residues derived from (+)-5-MeCDE corresponds to adduct conformations which are similar to those obtained from the binding of the highly tumorigenic trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene stereoisomer and other highly active bay-region diol epoxide derivatives to DNA. These findings provide further evidence that there is a correlation between DNA adduct conformation and biological activities for these series of polycyclic aromatic diol epoxide derivatives with R,S,S,R absolute configuration and which are known to bind predominantly to N2 of guanine.",
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N2 - The conformations of adducts derived from the covalent binding of four different isomeric diol epoxide derivatives of 5- or 6-methylchrysene to native double-stranded calf thymus DNA were studied by linear dichroism techniques. Out of four isomers investigated here, only the R,S,S,R enantiomer of anti-1,2-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-5-methyl chrysene, (+)-5-MeCDE, is highly tumorigenic and mutagenic toward Salmonella typhimurium TA100; the S,R,R,S enantiomer, (-)-5-MeCDE, and the corresponding R,S,S,R and S,R,R,S enantiomers of anti-1,2,-dihydroxy-3,4-epoxy-1,2,3,4-tetrahydro-6-methylchrysene are non-tumorigenic and much less mutagenic than (+)-5-MeCDE. [Melikian et al., (1988) Cancer Res., 48, 1781 -1787] Only the DNA adducts derived from the binding of (+)-5-MeCDE are characterized by a pronounced positive linear dichroism signal at 308 nm due to the phenanthrenyl residue which is tilted at an angle of 45-48° with respect to the average orientations of the axes of unoriented DNA segments. The phenanthrenyl residues derived from the covalent binding to DNA of the other three inactive or less active isomers appear to be unoriented. The defined orientation of the covalently bound phenanthrenyl residues derived from (+)-5-MeCDE corresponds to adduct conformations which are similar to those obtained from the binding of the highly tumorigenic trans-7,8-dihydroxy-anti-9,10-epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene stereoisomer and other highly active bay-region diol epoxide derivatives to DNA. These findings provide further evidence that there is a correlation between DNA adduct conformation and biological activities for these series of polycyclic aromatic diol epoxide derivatives with R,S,S,R absolute configuration and which are known to bind predominantly to N2 of guanine.

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