Calculations Related to the Reactivity of Polycyclic Aromatic Hydrocarbon Episulfides

2008

CMC

Polycyclic aromatic hydrocarbons (PAHs) are widespread environmental pollutants well known as mutagenic/carcinogenic agents. This review will discuss recent theoretical studies regarding the stability and reactivity of ultimate carcinogenic metabolites from PAHs, focusing on their diol epoxide and amine derivatives. Geometrical and electronic features will be analyzed in order to obtain structure-activity relationships. Charge delocalization modes (positive charge density distribution), substituent effects, and conformational aspects will be considered. Computed properties will be compared with the available biological activity data. Correlations between experimental mutagenic potencies reported in the literature and calculated reaction energies and electronic properties will be shown. Heteroaromatic compounds (aza-PAHs, thia-PAHs, and heteroaromatic amines) will also be examined. To model the important step of covalent adduct formation, calculation of the adducts resulting from bond formation between some of these electrophilic intermediates and nucleotide bases (guanine, cytosine) will be described.

Section: Carbocations From Miscellaneous Het-ero-pahssupporting

confidence: 91%

Quantum Chemical Studies on Ultimate Carcinogenic Metabolites from Polycyclic Aromatic Hydrocarbons

2008

CMC

“…In relation to this, good correlations have been obtained between the calculated relative energies for carbocation formation from various PAHs and their reactivity towards nucleic acid (24)(25)(26)(27)(28). Moreover, a clear relationship was observed between the extent of charge delocalization in the carbocation (assessed by the decrease in positive charge at the carbocationic centre within series of compounds) and the ease of its formation (24)(25)(26).…”

Section: (1)mentioning

confidence: 99%

“…Very good agreement with the experimental reactivities of several PAH derivatives have been shown by recent quantum-mechanical calculations when applied to the study of the carcinogenic pathways of these compounds (24)(25)(26)(27)(28). Besides, modeling studies of biological electrophiles from PAHs by DFT methods have yielded appropriate descriptions of the NMR features and charge delocalization modes of their resulting carbocations (29)(30)(31)(32)(33)(34)(35)(36)(37)(38)(39).…”

Section: Introductionmentioning

confidence: 99%

“…As in previous computational studies (24)(25)(26)(27)(28), these intermediates have proven to generate the same reactivity trends as their DE analogs, while requiring considerably less computational time. The present study was inspired by our earlier stable ion work on the BA carbocations (31) and sets the stage for a more comprehensive structure/reactivity study with a larger set of regioisomeric mono-and dialkylated BAs.…”

Section: Introductionmentioning

confidence: 99%

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

Laali

2006

Chem. Res. Toxicol.

Structure-reactivity relationships and substituent effects on carbocation stability in benzo [a] anthracene (BA) derivatives have been studied computationally at the B3LYP/6-31G* and MP2/6-31G** levels. Bay-region carbocations are formed by O-protonation of the 1,2-epoxides in barrierless processes. This process is energetically more favored as compared to carbocation generation via zwitterion formation/O-protonation, via single electron oxidation to generate a radical cation, or via benzylic hydroxylation. Relative carbocation stabilities were determined in the gas phase and in water as solvent (PCM method). Charge delocalization mode in the BA carbocation framework was deduced from NPA-derived changes in charges, and substitution by methyl or fluorine was studied at different positions selected on basis of the carbocation charge density. A bayregion methyl group produces structural distortion with consequent deviation from planarity of the aromatic system, which destabilizes the epoxide, favoring ring opening. Whereas fluorine substitution at sites bearing significant positive charge leads to carbocation stabilization by fluorine p-π back-bonding, a fluorine atom at a ring position which presented negative charge density leads to inductive destabilization. Methylated derivatives are less sensitive to substituent effects as compared to the fluorinated analogues. Although the solvent decreases the exothermicity of the epoxide ring opening reactions due to greater stabilization of the reactants, it provokes no changes in relative reactivities. Relative energies in the resulting bay-region carbocations are examined taking into account the available biological activity data on these compounds. In selected cases, quenching of bay-region carbocations was investigated by analyzing relative energies (in the gas phase and in water) and geometries of their guanine adducts formed via covalent bond formation with the exocyclic amino group and with the N-7.

“…Recent quantum‐chemical calculations concerning the carcinogenic pathway of PAH epoxides and diol epoxides have shown very good agreement with the experimental reactivity of this type of compounds 9. Furthermore, the reactivity of the less known sulfur derivatives episulfides and diol episulfides was also correctly described by the same calculation methods 10. Taking this into account, it would be interesting to determine the factors that cause the higher mutagenic activity of the imine analogs.…”

Section: Introductionmentioning

confidence: 75%

Theoretical study concerning the reactivity of imine derivatives of polycyclic aromatic hydrocarbons

2003

J Comput Chem

The opening reaction of N-protonated polycyclic aromatic hydrocarbon imines has been computed by means of ab initio, density functional, and semiempirical methods of calculation. Imines are predicted to be more stable than the corresponding O-protonated derivatives, epoxides and diol epoxides. On the other hand, the activated N-methanesulfonylbenzene imine presented more favorable DeltaE( not equal ) and DeltaE(r) for ring opening due to the effect of hydrogen-bond interactions. Anti and syn trans-diol benzene imines did not show a different behavior from the unsubstituted imine. According to these calculations, bay-region, fjord-region, and bay-region methyl-substituted compounds opened more easily among the imine derivatives, following the same reactivity pattern as the oxygen analogs. The exothermicity of the opening process correlated with the charge delocalization in the resulting carbocation.