Structure‐activity relationships (SARs) among mutagens and carcinogens: A review

Abstract

This review is an introduction to methods for evaluating structure-activity relationships (SARs), and, in particular, to those methods that have been applied to study mutagenicity and carcinogenicity. A brief history and some background material on the earliest attempts to correlate molecular structure and biological activity are included. Most of the discussion focuses on modern methods utilizing extrathermodynamic and physical property variables such as the Hansch method and SIMCA, and approaches based on molecular connectivity such as the ADAPT, CASE, and Enslein methods. In general, the latter class is potentially the most useful in the study of the large and structurally diverse databases so often encountered in the study of mutagenicity and carcinogenicity. They also are not very sensitive to lab-to-lab variances in reported activities and outright misclassifications in activities of some compounds. This is chiefly because the statistical treatments used in these methods tend to dilute the importance of outliers. The methods using physicochemical and extrathermodynamic variables are especially important in relatively small, congeneric databases and can help fine-tune the role of physicochemical properties in mechanistic hypotheses. All of the above methods have been used to look at mutagenicity and carcinogenicity and some of the results reported in the literature are reviewed here. As far as specific methods go, ADAPT, CASE, SIMCA and the Enslein approach all seem to have similar classification powers (in the range of 75-95%), depending very much on the database studied. The emphasis in this review is on showing that the use of these computer-aided storage, retrieval and analysis techniques is a timely approach to predicting and even understanding the toxicity of environmental substances. However, each of the methods discussed is still under development, and their potential usefulness for predictive purposes is still being explored.

Evaluation of Dermal Irritancy Potential of Benzanthrone-Derived Dye Analogs: Structure Activity Relationship

“…The lipophilic dyes containing different functional groups, e.g. amino, imino, phenolic, thiol, make the molecule electrophilic, leading to covalent binding with protein and nucleic acid [29][30][31].…”

Toxic Substances Control In The 1990s: Are We Poisoning Ourselves With Low Level Exposures

“…SAR relies on the chemical structure of a molecule to infer its toxicity (22). The fundamental hypothesis is that identifiable aspects of molecular structure give rise to both acute and chronic toxicity.…”

A computerized connectivity approach for analyzing the structural basis of mutagenicity in Salmonella and its relationship with rodent carcinogenicity

“…On this basis, the program makes a prediction for a different set of chemicals (test set). Our software program can be classified among computerized "connectivity" approaches (i.e., based on the atomic structure of molecules, including bond connections, as defined by Frierson et al [1986]), and among "correlative SAR approaches" (i.e., using correlative techniques to identify molecular descriptors, to explain biological activity or inactivity, as defined by Richard [1994]), in opposition to "rule-based" SAR approaches such as the Ashby structural alerts model. According to these authors, this type of approach is potentially useful to analyze large databases of noncongeneric chemicals.…”