Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes

Hatch, Frederick T.; Colvin, Michael E.; Seidl, Edward T.

doi:10.1002/(sici)1098-2280(1996)27:4<314::aid-em6>3.0.co;2-c

Cited by 41 publications

(58 citation statements)

References 31 publications

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“…The low LUMO energy and DeltaE in flavonoids that are potentially planar and more potent inhibitors of mutagenesis indicates that these flavonoids may function as soft electrophiles [Fleming, 1976]. This is similar to our previous finding that the high mutagenic potency of IQ and related cooking mutagens is associated with low LUMO energy [Hatch et al, 1996].…”

Section: Quantum Chemical Contributionscontrasting

confidence: 99%

“…This is in marked contrast to our previous findings on the mutagenic potency of 16 aminoimidazo-azaarenes, spanning seven orders of magnitude [Hatch et al, 1996] and 165 aromatic and heterocyclic amines spanning ten orders [Hatch and Colvin, 1997]. The narrower potency range, together with limited pairwise correlations, in this study probably contributes to the paucity of clear-cut statistical relationships.…”

Section: Limited Qsar Obtainedmentioning

confidence: 99%

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Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity

Hatch

Lightstone

Colvin

2000

Environ. Mol. Mutagen.

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The mutagenic/carcinogenic heterocyclic amines formed during the cooking of protein foods have been determined to be a potential risk to human health. Therefore, mitigation measures are beginning to be studied. A recent finding is that the induction of mutation in Salmonella by these amines can be inhibited by the addition of flavonoids to the assay. This study combines data on the inhibitory process with structural, ab initio quantum chemical, hydropathic, and antioxidant factors to develop a quantitative structure‐activity relationship (QSAR) database and statistical analysis. For 39 diverse flavonoids the inhibitory potency varied approximately 100‐fold. Three predictive variables, in order of decreasing contribution to variance, are: (1) a large dipole moment; (2) after geometric minimization of energy, a small departure from planarity (i.e., small dihedral angle between the benzopyran nucleus and the attached phenyl ring), and a low rotational energy barrier to achieving planarity; and (3) fewer hydroxyl groups on the phenyl ring. However, these variables account for less than half of the variance in inhibitory potency of the flavonoids. Frontier orbital energies and antioxidant or radical scavenging properties showed little or no relationship to potency. We conclude that interference by the flavonoids with cytochrome P450 activation of the promutagens is the probable mechanism for inhibition of mutagenesis, and suggest avenues for further research. Environ. Mol. Mutagen. 35:279–299, 2000 Published 2000 Wiley‐Liss, Inc.

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Section: Quantum Chemical Contributionscontrasting

confidence: 99%

Section: Limited Qsar Obtainedmentioning

confidence: 99%

Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity

Hatch

Lightstone

Colvin

2000

Environ. Mol. Mutagen.

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“…A number of QSAR studies of the AIA food mutagens have found that high mutagenic potency is predicted by low-energy lowest unoccupied molecular orbital (LUMO) [12,13]. Our results show a reasonably strong correlation between LUMO energy and observed mutagenic potential of several heterocyclic amine mutagens (Figure 4).…”

Section: Qsar Studiessupporting

confidence: 63%

Mutagenic potency of food-derived heterocyclic amines

Felton

Knize

et al. 2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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The understanding of mutagenic potency has been primarily approached using "quantitative structure activity relationships" (QSAR). Often this method allows the prediction of mutagenic potency of the compound based on its structure. But it does not give the underlying reason why the mutagenic activities differ. We have taken a set of heterocyclic amine structures and used molecular dynamic calculations to dock these molecules into the active site of a computational model of the cytochrome P-450 1A1 enzyme. The calculated binding strength using Boltzman distribution constants was then compared to the QSAR value (HF/6-31G* optimized structures) and the Ames/Salmonella mutagenic potency. Further understanding will only come from knowing the complete set of mutagenic determinants. These include the nitrenium ion half-life, DNA adduct half-life, efficiency of repair of the adduct, and ultimately fixation of the mutation through cellular processes. For two isomers, PhIP and 3-Me-PhIP, we showed that for the 100-fold difference in the mutagenic potency a 5-fold difference can be accounted for by differences in the P450 oxidation. The other factor of 20 is not clearly understood but is downstream from the oxidation step. The application of QSAR (chemical characteristics) to biological principles related to mutagenesis is explored in this report.3

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“…According to this, several studies have developed quantitative structure-activity relationships (QSARs) intending to correlate quantitative bacterial mutagenicity and carcinogenicity data for AAs and HAs with calculated or observed properties of the amines or their derived nitrenium ions [12][13][14][15][16][17][18][19][20][21][22][23][24]. Some of them have proposed that mutagenicity increases with the rate of nitrenium ion formation from their precursors, i.e., with a higher nitrenium intermediate stability, as computed with the semiempirical methods AM1, PM3 or PM5 [14][15][16][17][18][19].…”

Section: Introductionmentioning

confidence: 94%

“…Some of them have proposed that mutagenicity increases with the rate of nitrenium ion formation from their precursors, i.e., with a higher nitrenium intermediate stability, as computed with the semiempirical methods AM1, PM3 or PM5 [14][15][16][17][18][19]. On the other hand, multiple variable models including higher level ab initio calculated variables related to nitrenium ion stability have suggested that these variables are of only limited use in regression models [12,13,[20][21][22], questioning the importance of nitrenium ion stability in determining the mutagenic potency of amines [22].…”

Section: Introductionmentioning

confidence: 94%

Carcinogenic carbocyclic and heterocyclic aromatic amines: A DFT study concerning their mutagenic potency

Borosky

2008

Journal of Molecular Graphics and Modelling

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Structural and quantum chemical factors affecting mutagenic potency of aminoimidazo-azaarenes

Cited by 41 publications

References 31 publications

Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity

Quantitative structure-activity relationship of flavonoids for inhibition of heterocyclic amine mutagenicity

Mutagenic potency of food-derived heterocyclic amines

Carcinogenic carbocyclic and heterocyclic aromatic amines: A DFT study concerning their mutagenic potency

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