The Effect of Fluoro Substituents on Reactivity of 7-Methylbenz[a]anthracene Diol Epoxides

Abstract

The present study has examined potential mechanisms for the influence of F-substituents on the biologic activity of methylbenz[a]anthracenes. DNA adducts derived from reaction of the racemic bay-region anti-diol epoxides of 7-methylbenz[a]anthracene, and its 9- and 10- fluoro derivatives, with calf thymus DNA in vitro were partially characterized. All three hydrocarbon diol epoxides produced similar DNA adduct profiles upon reaction with calf thymus DNA in vitro that were composed of two deoxyganosine and two deoxyadenosine adducts (tentatively identified as trans addition products). The extent of covalent binding to calf thymus DNA, as estimated by 32P-postlabeling, was similar for all three diol epoxides. The reactivity of the unsubstituted and 10-F-substituted diol epoxide was further assessed by measuring overall pseudo-first-order rate constants for hydrolysis in water or 0.1 M Tris-HCl buffer, pH 7.0, and in the presence or absence of native or denatured DNA. The rate constant for hydrolysis of 7-methylbenz[a]anthracene diol epoxide in the absence of DNA was similar to that of 10-F-7-methylbenz[a]anthracene diol epoxide (t1/2 = 138 min vs 115 min in water, respectively, and 93 vs 83 min in 0.1 M Tris-HCl buffer, respectively). In addition, the presence of DNA accelerated hydrolysis rates to similar extents for both diol expoxides. The skin tumor-initiating activities of the 9- and 10-F-substituted 3,4-diols of 7-methyl-, 12-methyl-, and 7,12-dimethylbenz[a]anthracene were determined in SENCAR mice. The presence of F-substituents in the 9- or 10- position did not enhance or in some cases reduced the tumor-initiating activity of the 3,4-diols of these hydrocarbons. Collectively, these results, as well as previous results from our laboratory, suggest that the influence of a F-substituent at position 10 of the benz[a]anthracene nucleus is not due to increased or altered reactivity of the bay-region diol epoxide but rather likely on the initial formation of the 3,4-diol.

Quantum Chemical Studies on Ultimate Carcinogenic Metabolites from Polycyclic Aromatic Hydrocarbons

“…Similar F-substitution effects were also observed for the 7-and 12-monomethyl analogues of BA [46,[50][51][52]. Effect of a fluoro substituent at C-9 and C-10 on tumorigenicity of 7-MBA-3,4-diol, 12-MBA-3,4-diol, and 7,12-DMBA-3,4-diol was also studied [51]. It was argued that F-substitution at C-10 in BA increases the metabolic formation of the 3,4-diol, with no significant effect on the reactivity of the bay-region anti-DE [51].…”

“…For other regioisomeric fluoro derivatives of 7,12-DMBA, there was no significant change in activity [44,47]. Similar F-substitution effects were also observed for the 7-and 12-monomethyl analogues of BA [46,[50][51][52]. Effect of a fluoro substituent at C-9 and C-10 on tumorigenicity of 7-MBA-3,4-diol, 12-MBA-3,4-diol, and 7,12-DMBA-3,4-diol was also studied [51].…”

Carbocations from Oxidized Metabolites of Benzo[a]anthracene: A Computational Study of Their Methylated and Fluorinated Derivatives and Guanine Adducts

“…The 10-F derivative was less reactive than nonfluorinated 7-MBA, this fact being in contrast with the experimental tumorigenic activities. However, subsequent studies have suggested that the influence of fluorine at C-10 of BA is not due to increased reactivity of the bay-region DE but rather likely on the initial formation of the 3,4-diol (21). Both 10-F-7-MBA and 7-MBA afforded ΔE r s more exothermic than 9-F-7-MBA, in accord with the biological activity of these derivatives (16,(20)(21)(22).…”

“…However, subsequent studies have suggested that the influence of fluorine at C-10 of BA is not due to increased reactivity of the bay-region DE but rather likely on the initial formation of the 3,4-diol (21). Both 10-F-7-MBA and 7-MBA afforded ΔE r s more exothermic than 9-F-7-MBA, in accord with the biological activity of these derivatives (16,(20)(21)(22). On the other hand, F-substitution at a position with negative charge density (C-5) decreased the exothermicity of the opening reaction, while 7-FBA also gave a less favored value than 7-MBA, both results being in agreement with their reported relative tumorigenicities (23,22).…”

Influence of structural and functional modifications of selected genotoxic carcinogens on metabolism and mutagenicity – a review

“…Also, substitution of an F-atom at C-11, the 'peri' position of 5-methylchrysene was found to reduce the tumour-initiating activity of the parent compound [52,63]. In contrast, markedly enhanced tumour-initiating and mutagenic activity was reported in case of fluorinated DMBA and 7-MBA containing a fluorine atom in C-10 position [64].…”