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Machine learning predictive classification models for the carcinogenic activity of activated metabolites derived from aromatic amines and nitroaromatics

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Abstract

A 3D-QSAR study based on DFT descriptors and machine learning calculations is presented in this work. Our goal has been to build predictive models for classifying the carcinogenic activity of a set of aromatic amines (AA) and nitroaromatic (NA) compounds. As the main result, we stress that calculations must consider both the activated metabolites (derived from AA and NA species) and the water solvent to obtain reliable predictive classification models. We have obtained eight decision tree models that presented an accuracy of over 90% by using either Gázquez-Vela chemical potential (μ⁺) or the chemical hardness (η).

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... In addition to these conventional descriptors, the values of modified chemical potential and electrophilic index proposed by Gazquez et al. (2007) were incorporated. This choice was influenced by recent evidence suggesting their utility in classifying the carcinogenic activity of activated metabolites derived from nitroaromatics (Halabi et al. 2022). ...
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... [63,64] Terephthalic acid (TPA) is used as a scavenger of •OH for the investigation of the mechanism of the electrocatalytic process. [65] Figure [66,67] (Red marked in Figure S16, Supporting Information) becomes less, and these intermediates of small molecule products can possibly be further converted into CO 2 , H 2 O, and ammonium ions. The possible degradation route is shown in Figure S15 (Supporting Information). ...
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Four process streams derived from the EDS† direct coal liquefaction process were evaluated in two in vitro assays to screen for carcinogenic potential: the Salmonella/mammalian microsome mutagenicity assay and the Syrian hamster embryo morphologic transformation assay. Three high boiling liquids (two recycle solvents, nominal boiling range 200–425°C; and a fuel oil blend, nominal boiling range 200–538°C) were active in both assays. A hydrotreated naphtha sample (<200°C) was not active in either. The Salmonella data agreed qualitatively with results of dermal carcinogenesis studies; however, quantitative differences as measured by the estimation of mutagenic potency were apparent. The lack of quantitative agreement may have been related to the fact that the dermal carcinogenic activity of coal-derived synthetic fuels is predominantly associated with neutral polycyclic aromatic hydrocarbons, whereas activity in the Salmonella assay is strongly influenced by the presence of aromatic amines and nitroaromatic compounds. Two modifications of the Salmonella assay—detergent disperson and hamster S9 activation—were examined. These techniques improved assay performance for some but not all of the coal liquids. The differences in response may have been related to compositional differences in the various liquids.
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In this paper we present the expandability and flexibility features of the VEGA program (downloadable free of charge at http://www.ddl.unimi.it), for the development of custom applications, using it as a multipurpose graphical environment. VEGA can be customized using both plug-in architecture and script programming. The first is useful to add new features and functions, using homemade routines, written with the VEGA Plug-in Development Kit (SDK). With the second approach it is possible to design scripts in VEGA, using the REBOL language, in order to (1) add new functions or customize existing ones; (2) automate common procedures; and (3) allow network communications, by creating a bridge between VEGA and other applications (or other PCs) through the TCP/IP protocol.
Article
Mutagens in urban air pollution come from anthropogenic sources (especially combustion sources) and are products of airborne chemical reactions. Bacterial mutation tests have been used for large, multi-site, and/or time series studies, for bioassay-directed fractionation studies, for identifying the presence of specific classes of mutagens, and for doing site- or source-comparisons for relative levels of airborne mutagens. Early research recognized that although carcinogenic PAHs were present in air samples they could not account for the majority of the mutagenic activity detected. The mutagenicity of airborne particulate organics is due to at least 500 identified compounds from varying chemical classes. Bioassay-directed fractionation studies for identifying toxicants are difficult to compare because they do not identify all of the mutagens present, and both the analytical and bioassay protocols vary from study to study. However, these studies show that the majority of mutagenicity is usually associated with moderately polar/highly polar classes of compounds that tend to contain nitroaromatic compounds, aromatic amines, and aromatic ketones. Smog chamber studies have shown that mutagenic aliphatic and aromatic nitrogen-containing compounds are produced in the atmosphere when organic compounds (even non-mutagenic compounds) are exposed to nitrogen oxides and sunlight. Reactions that occur in the atmosphere, therefore, can have a profound effect on the genotoxic burden of ambient air. This review illustrates that the mutagenesis protocol and tester strains should be selected based on the design and purpose of the study and that the correlation with animal cancer bioassay results depends upon chemical class. Future emphasis needs to be placed on volatile and semi-volatile genotoxicants, and on multi-national studies that identify, quantify, and apportion mutagenicity. Initial efforts at replacing the Salmonella assay for ambient air studies with some emerging technology should be initiated.
Article
For Abstract see ChemInform Abstract in Full Text.
Article
By introducing an electron bath that represents the chemical environment in which a chemical species is immersed, and by making use of the second-order Taylor series expansions of the energy as a function of the number of electrons in the intervals between N - 1 and N, and N and N + 1, we show that the electrodonating (omega-) and the electroaccepting (omega+) powers may be defined as omega-/+ = (mu-/+)2/2eta-/+, where mu-/+ are the chemical potentials and eta-/+ are the chemical hardnesses, in their corresponding intervals. Approximate expressions for omega- and omega+ in terms of the ionization potential I and the electron affinity A are established by assuming that eta- = eta+ = eta = mu+ - mu-. The functions omega-/+(r) = omega-/+f -/+(r), where f -/+(r) are the directional Fukui functions, derived from a functional Taylor series for the energy functional truncated at second order, represent the local electrodonating and electroaccepting powers.
Article
The electrophilic/nucleophilic character of a series of captodative (CD) ethylenes involved in polar cycloaddition reactions has been studied using DFT methods at the B3LYP/6-31G(d) level of theory. The transition state structures for the electrophilic/nucleophilic interactions of two CD ethylenes toward a nucleophilically activated ethylene, 2-methylene-1,3-dioxolane, and an electrophilically activated ethylene, 1,1-dicyanoethyelene, have been studied, and their electronic structures have been characterized using both NBO and ELF methods. Analysis of the reactivity indexes of the CD ethylenes explains the reactivity of these species. While the electrophilicity of the molecules accounts for the reactivity toward nucleophiles, it is shown that a simple index chosen for the nucleophilicity, Nu, based on the HOMO energy is useful explaining the reactivity of these CD ethylenes toward electrophiles.
Aromatic-amines and nitroaromatic hydrocarbons as environmental carcinogens - metabolic-activation, carcinogen-DNA adduct formation, and methods for adduct detection
  • Kadlubar
Kadlubar, F.F., 1983. Aromatic-amines and nitroaromatic hydrocarbons as environmental carcinogens -metabolic-activation, carcinogen-DNA adduct formation, and methods for adduct detection. Br. J. Cancer 48 (pp. 111-111).
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Geerlings, P., Chamorro, E., Chattaraj, P.K., De Proft, F., Gazquez, J.L., Liu, S.B., Morell, C., Toro-Labbe, A., Vela, A., Ayers, P., 2020. Conceptual density functional theory: status, prospects, issues. Theor. Chem. Accounts 139, 18.
Nitroaromatic compounds, from synthesis to biodegradation. Microbiol
IARC, 2021. Some Aromatic Amines and Related Compounds. IARC Monographs on the Identification of Carcinogenic Hazards to Humans, vol. 127. International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon Cedex 08, France. Ju, K.S., Parales, R.E., 2010. Nitroaromatic compounds, from synthesis to biodegradation. Microbiol. Mol. Biol. Rev. 74 (pp. 250-+).