Frontier Orbitals in Chemical and Biological Activity: Quantitative Relationships and Mechanistic Implications*

Lewis, David F.

doi:10.1081/dmr-100101943

Cited by 44 publications

(29 citation statements)

References 60 publications

(79 reference statements)

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“…In general, it is apparent that the frontier orbital energies, E H and E L , or the energy gap between them (namely, DE) correlate closely with mutagenicity of these compounds. To an extent, this may equate with electrophilicity because electron uptake rates also depend on frontier orbital energies (E L and DE) as reported in this work and previously [16,17]. However, in some cases, frontier orbital electron densities on key atoms in the molecule are also involved, thus indicating specific sites of metabolic activation in structurally related series.…”

Section: Discussionsupporting

confidence: 72%

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A quantitative structure-activity relationship (QSAR) study of mutagenicity in several series of organic chemicals likely to be activated by cytochrome P450 enzymes

Lewis¹,

Ioannides²,

Parke³

2003

Teratog. Carcinog. Mutagen.

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The results of quantitative structure-activity relationship (QSAR) studies on six series of compounds exhibiting indirect mutagenic activity are reported. These findings demonstrate the importance of frontier orbital energies and, in some cases, frontier orbital electronic populations to overall mutagenicity in diverse polyaromatic hydrocarbons, benzidines and aminobiphenyls, benzonitrofurans, nitrogenous cooked-food mutagens, benzanthracenes, and chrysenes. The correlations between structural parameters and mutagenic potency vary from R=0.81 to R=0.97, and these findings are discussed in the context of possible molecular mechanisms of mutagenicity. In particular, it is generally regarded that cytochrome P450-mediated activation of polyaromatic hydrocarbons and their amino derivatives plays an important role in mutagenic activity. In this respect, it is apparent that enzymes of the cytochrome P4501 (CYP1) family are closely associated with the metabolic activation of polyaromatic mutagens and carcinogens via the generation of reactive intermediates (usually electrophilic in nature) that attack DNA. The findings presented in this study indicate that QSAR analyses on several series of compounds are consistent with the known evidence of procarcinogen activation mechanisms, particularly for polyaromatic hydrocarbons and their heterocyclic/amino derivatives, pointing to the importance of frontier orbital energy values in particular.

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Section: Discussionsupporting

confidence: 72%

“…From inspection of 7. Diverse compounds [16,17] ðaÞ log k e ¼ À 0:73E L À 0:13E 2 L À 0:05 ðAE 0:13Þ ðAE0:01Þ 26 0.67 0.86 31.7…”

Section: Resultsmentioning

confidence: 99%

A quantitative structure-activity relationship (QSAR) study of mutagenicity in several series of organic chemicals likely to be activated by cytochrome P450 enzymes

Lewis¹,

Ioannides²,

Parke³

2003

Teratog. Carcinog. Mutagen.

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“…The interaction of frontier orbitals (HOMO, highest occupied molecular orbital and LUMO, lowest unoccupied molecular orbital) has been shown to play a role in chemical reactivity (Chan et al, 2007a;Osman et al, 1988). Generally, HOMO of the nucleophile reacts with the LUMO of the electrophilic species (Lewis, 1999), where LUMO typically acts as an electron acceptor in chargetransfer interactions (Boudon et al, 1988). Previous work from our laboratory showed that E LUMO was also a good descriptor for hepatotoxic effects for a series of pbenzoquinones which are also electrophilic compounds that act via Michael-type mechanism (Chan et al, 2007a).…”

Section: Discussionmentioning

confidence: 99%

Structure–activity relationships for hepatocyte toxicity and electrophilic reactivity of α,β‐unsaturated esters, acrylates and methacrylates

Chan

O’Brien

2008

J of Applied Toxicology

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Covalent binding of reactive electrophiles to cellular targets is a molecular interaction that has the potential to initiate severe adverse biological effects. Therefore, electrophile reactivity towards biological nucleophiles could serve as an important correlate for toxic effects such as hepatocyte death. To determine if reactivity correlates with rat hepatotoxicity, alpha,beta-unsaturated esters, consisting of acrylates and methacrylates, that are inherently electrophilic and exhibit widely varying degrees of reactivity were investigated. Reactivity was measured using simple assays with glutathione and butylamine as surrogates for soft thiol and hard amino biological nucleophile targets. A linear relationship was observed between hepatotoxicity and thiol reactivity only, while no amine reactivity was observed. Structure-activity relationships were also investigated, with results showing toxicity was well modeled by electronic parameters E(LUMO) and partial charge of the carbon atoms in the reactive center. No relationship was observed between toxicity and logP. These results suggest that differences in hepatocyte toxicity of acrylates and methacrylates can be related to their electrophilic reactivity which corresponds to their ability to deplete GSH and protein thiols.

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“…This notion was mentioned in many early works on the FAB‐induced reduction,20, 23, 24 but the quantitative calculation data were not reported, obviously because of unavailability of computational facilities for rather complicated molecular calculations at that time. Nowadays, frontier orbital analysis finds wide applications in studies of chemical reactivity and structure‐activity relationships for biomolecules 41…”

Section: Introductionmentioning

confidence: 99%

Evaluation of the reduction of imidazophenazine dye derivatives under fast‐atom‐bombardment mass‐spectrometric conditions

et al. 2005

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Satellite [M + 2](+*) and [M + 3](+) peaks accompanying the common peak of the protonated molecule [M + H](+) that are known to indicate the occurrence of a reduction process were observed in the fast atom bombardment (FAB) mass spectra of imidazophenazine dye derivatives in glycerol matrix. The distribution of the abundances in the [M + nH](+) peak group varied noticeably for different derivatives. This indicated different levels of the reduction depending on the different structure variations of the studied molecules. In the search for correlations between the mass spectral pattern and the structural features of the dyes, ab initio HF/6-31++G** quantum chemical calculations were performed. They revealed that the abundances of the [M + 2](+*) and [M + 3](+) ions show growth proportional to the decrease of the energy of the lowest unoccupied molecular orbital, i.e. proportional to the increase of the electron affinity of the dye molecule. A method for rapid screening of reductive properties of sets of dye derivatives on the basis of the FAB mass spectral data is discussed.

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Frontier Orbitals in Chemical and Biological Activity: Quantitative Relationships and Mechanistic Implications*

Cited by 44 publications

References 60 publications

A quantitative structure-activity relationship (QSAR) study of mutagenicity in several series of organic chemicals likely to be activated by cytochrome P450 enzymes

A quantitative structure-activity relationship (QSAR) study of mutagenicity in several series of organic chemicals likely to be activated by cytochrome P450 enzymes

Structure–activity relationships for hepatocyte toxicity and electrophilic reactivity of α,β‐unsaturated esters, acrylates and methacrylates

Evaluation of the reduction of imidazophenazine dye derivatives under fast‐atom‐bombardment mass‐spectrometric conditions

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