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

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-methylchrysene, (+)-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 degrees 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.

Site-specific adducts derived from the binding of anti-5-methylchrysene diol epoxide enantiomers to DNA: Synthesis and characteristics

“…However, the shoulder between 300 and 315 nm in the modified oligonucleotide is characteristic of the aromatic phenanthrenyl residue. The characteristics of the absorption spectra of analogous covalent 5-MeCDE-native DNA adducts have been discussed previously (32). Figure 4B.…”

“…The slower electrophoretic mobilities of the (+)-enantiomermodified duplexes appear to be related to either greater extents of static bending, higher flexibilities at the sites of the lesions, or to differences in the hydration of the non-polar pyrenyl residues (42). Interestingly, these conclusions are supported by changes in persistence lengths (measured by linear dichroism techniques) caused by the binding of these two BPDE (23,(43)(44)(45) and 5-MeCDE enantiomers (32,46) to native DNA, or to synthetic polynucleotides. The persistence lengths of the (+)enantiomer-modified DNA are significantly reduced relative to unmodified DNA, while those of adducts derived from the (-)-enantiomers are not changed to any significant extent.…”

Comparative tumorigenicity of dimethylchrysenes in mouse skin

“…Human exposure to these compounds, many of which are potent carcinogens, is widespread (1). The molecular shape of this diol epoxide gives it unique DNA binding and carcinogenic properties (5)(6)(7). This pathway is illustrated in Figure 1 QS93-22~~/92/27Q5-Q237$03.QQ/Q strongest carcinogen among the six monomethylchrysenes (3-6).…”

“…In a similar manner, alkene 6 was prepared in 29% yield from l-naphthylacetic acid and p-tolualdehyde (3) (B) 5-Carbomethoxy-7-methylchrysene (7). Dry air was bubbled through a solution of 4 (0.8 g, 2.65 mmol) and 5 mg of Iz in dry benzene.…”

Solution Conformation of the (-)-trans-anti-5-Methylchrysene-dG Adduct opposite dC in a DNA Duplex: DNA Bending Associated with Wedging of the Methyl Group of 5-Methylchrysene to the 3'-Side of the Modification Site

“…The recent availability of homogeneous (+)and (-)-trans-anti-[MC]-dG oligodeoxyribonucleoside adducts in sufficient quantities needed for two-dimensional NMR structural studies (Xu, 1994) provides us with the opportunity to study solution structures of adducts derived from these two -5-MeCDE enantiomers having strikingly different biological activities. The conformations of adducts derived from the covalent binding of (+)-anfz-5-MeCDE and (-)-aniz-5-MeCDE to native DNA by UV spectroscopic methods have been previously studied, but the orientational characteristics of the (-)-azifz'-5-MeCDE-DNA adducts could not be established, most likely because of a multiplicity of adducts (Geacintov et al, 1990). The results of this investigation represent the first results on the conformational characteristics of the adduct derived from the chemical reaction of a methylated PAH diol epoxide with DNA.…”