Assessment of the propensity for covalent binding of electrophiles to biological substrates.

Abstract

Electrophilic character is associated with the ability of external agents to interact with centers of electron density in biological macromolecules and to cause the interruption or alternation of normal activity. With the observation of site specificity in mutagenic events. Pearson's hard/soft acid-based (HSAB) theory is presented as a useful concept in correlating chemical observations in the absence of detailed direct knowledge of the process. Methods for the evaluation of carbon electrophiles (e.g., carbocation character) as reactants are reviewed as potential physical parameters that could be applied in developing quantitative structure-activity relationships.

Metabolism and disposition of inorganic arsenic in laboratory animals and humans

“…One can predict from the mechanistic hypothesis just described that arsenic is not genotoxic in the sense of causing point mutations on DNA, consistent with the hard Lewis base properties of the nucleophilic sites in DNA (Carlson, 1990). Arsenic may alter genetic material through interaction with important regulatory proteins that affect gene expression such as the DNA polymerases and possibly cytoskeletal proteins involved in cytoskeletal organisation and DNA synthesis (Li et al, 1991).…”

“…Based on studies with mice, the concentration of arsenic decreases fairly rapidly in most organs. A specific retention of arsenic in the thyroid is interesting in view of the suggested goitrogenic effect of inorganic arsenic and may reflect some soft Lewis base ligand-type properties for iodide (Carlson, 1990) as suggested for sulphur.…”

“…The affinity of trivalent arsenic for sulphur is well known (see NAS, 1977 for discussion), and since the involvement of an arsenic cation seems unlikely this can be viewed as an associative pathway analogous to Sn2 displacements in organic chemistry. The geometry and electronic state (coordination number and unsaturation) apparently invite nucleophilic attack by soft Lewis base ligands such as sulphur (Carlson, 1990). Reactions of this type (see general equation, Figure l) may explain the interactions of trivalent arsenic (considered the more toxic form) with nonprotein thiol compounds such as dimercaprol (BAL) and with various thiol groups in proteins, nucleophilic methylating agents such as possibly methylcobalamin, etc.…”

Assessment of the genotoxic and carcinogenic potentials of 3‐aminothiophene derivatives using in vitro and in silico methodologies

“…5), but the results associated to the Ames test and Comet assay did not support this hypothesis as no reactivity towards DNA has been observed (Carlson, 1990;Gregus and Klaassen, 2001). Concerning CypScore, the program did not detect double bonds likely to undergo epoxidation (model 3).…”

“…5). In fact, soft electrophiles react with soft nucleophiles, such as the sulphur atom of thiols found in cysteine residues of proteins and peptides like glutathione (Carlson, 1990;Gregus and Klaassen, 2001).…”