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Structure–Activity Relationships in Nitro-Aromatic Compounds

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Practical Aspects of Computational Chemistry

Abstract

Many nitro-aromatic compounds show mutagenic and carcinogenic properties, posing a potential human health risk. Despite this potential health hazard, nitro-aromatic compounds continue to be emitted into ambient air from municipal incinerators, motor vehicles, and industrial power plants. As a result, understanding the structural and electronic factors that influence mutagenicity in nitro-aromatic compounds has been a long standing objective. Progress toward this goal has accelerated over the years, in large part due to the synergistic efforts among toxicology, computational chemistry, and statistical modeling of toxicological data. The concerted influence of several structural and electronic factors in nitro-aromatic compounds makes the development of structure–activity relationships (SARs) a paramount challenge. Mathematical models that include a regression analysis show promise in predicting the mutagenic activity of nitro-aromatic compounds as well as in prioritizing compounds for which experimental data should be pursued. A major challenge of the structure–activity models developed thus far is their failure to apply beyond a subset of nitro-aromatic compounds. Most quantitative structure–activity relationship papers point to statistics as the most important confirmation of the validity of a model. However, the experimental evidence shows the importance of the chemical knowledge in the process of generating models with reasonable applicability. This chapter will concisely summarize the structural and electronic factors that influence the mutagenicity in nitro-aromatic compounds and the recent efforts to use quantitative structure–activity relationships to predict those physicochemical properties.

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Acknowledgments

This research was supported by a grant from the ACS Petroleum Research Fund, Type DNI. The authors also thank the Department of Chemistry, Case Western Reserve University and the National Science Foundation, Academic Careers in Engineering and Science Program (NSF ACES) for financial support.

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Authors and Affiliations

  1. Department of Chemistry, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH, 44106, USA

    R. A. Vogt, S. Rahman & C. E. Crespo-Hernández

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  1. R. A. Vogt
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  2. S. Rahman
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  3. C. E. Crespo-Hernández
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Correspondence to C. E. Crespo-Hernández .

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Editors and Affiliations

  1. Dept. Chemistry, Jackson State University, J. R. Lynch St. 1325, Jackson, 39217, U.S.A.

    Jerzy Leszczynski

  2. Dept. Chemistry, Jackson State University, J. R. Lynch St. 1325, Jackson, 39217, U.S.A.

    Manoj K. Shukla

Glossary of Molecular Descriptors of Table 10.1

LUMO

Energy of the lowest unoccupied molecular orbital

log P

Logarithm of the octanol/water partition coefficient (descriptor pertaining to the hydrophobic character of the molecule)

log TA100

Mutagenic activity in TA100 strain cells

log TA98

Mutagenic activity in TA98 strain cells

LUMO

Energy of the lowest unoccupied molecular orbital

I a

Indicator variable for which the value is 1 if an acenthrylene ring is present; otherwise the value is zero

I l

Indicator variable for which the value is 1 for compounds with three or more fused rings; otherwise the value is zero

I and

Indicator variable for which the value is 1 for 1- and 2-methylindazole derivatives; otherwise the value is zero

log β

5.48 for the log TA98, and −5.7 for the log TA100

SOSIP

SOS induction potential in E.coli PQ37, measure the genotoxicity of the compound

q c2

Partial atomic charge on the carbon attached to the nitrogen of the nitro group

I sat

Indicator variable for which the value is 1 for saturated ring compounds; otherwise the value is zero

I 5,6

Indicator variable for which the value is 1 for compounds with substituents at the 5- or 6- position of 2-nitronaphtofurans and pyrenofurans; otherwise the value is zero

MR

Molecular refractivity, which is a measure of the substituent bulk for any substituents that are next to the nitro group, negative coefficient indicates its detrimental effect toward log SOSIP

TD50

Carcinogenic potency

\({\Omega^1}\mu_9^{\rm{H}},{\Omega^2}\mu_6^{\rm{H}},{\Omega^3}\mu_{15}^{\rm{H}} \)

Descriptors related to hydrophobicity

\( {\Omega^5}{\mu_1}\mu_4^{\rm{Dip}} \)

Descriptor related to dipole moment

\( {\Omega^4}{\mu_0}\mu_{15}^{\rm{GM}} \)

Descriptor related to the Gasteiger-Marsili charge

\( {\Omega^6}{\mu_0}\mu_{11}^{\rm{MR}},{\Omega^7}\mu_{11}^{\rm{MR}} \)

Descriptors related to molar refractivity (similar to MR above)

CIC1

Descriptor that gives information regarding molecular size; the more rings and nitro groups the more active the compound is

PW2

Descriptor related to the shape of the molecule; the less linear and more circular the molecule the more active the compound is

\( ^3{\chi^v} \) and \( ^2{\chi^{\rm{shape}}} \)

Descriptors that weights the contributions of compound’s size and shape to mutagenicity

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Vogt, R.A., Rahman, S., Crespo-Hernández, C.E. (2009). Structure–Activity Relationships in Nitro-Aromatic Compounds. In: Leszczynski, J., Shukla, M. (eds) Practical Aspects of Computational Chemistry. Springer, Dordrecht. https://doi.org/10.1007/978-90-481-2687-3_10

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