The effect of hydrophobicity upon the direct mutagenicity of N-acyloxy-N-alkoxyamides - bilinear dependence upon LogP

Title
The effect of hydrophobicity upon the direct mutagenicity of N-acyloxy-N-alkoxyamides - bilinear dependence upon LogP
Publication Date
2016
Author(s)
Glover, Stephen
( author )
OrcID: https://orcid.org/0000-0002-9344-8669
Email: sglover@une.edu.au
UNE Id une-id:sglover
Schumacher, Rhiannon R
Type of document
Journal Article
Language
en
Entity Type
Publication
Publisher
Elsevier BV
Place of publication
Netherlands
DOI
10.1016/j.mrgentox.2015.11.005
UNE publication id
une:18696
Abstract
N-Acyloxy-N-alkoxyamides 1 are direct-acting mutagens for which a bilinear QSAR has been established, which predicts with accuracy their activity in the Ames reverse mutation assay in 'Salmonella typhimurium' TA100, based upon their hydrophobicity (LogP), reactivity (pKA of the carboxylic acid of the N-carboxyl group) and TAFT steric parameters. From activity data for 55 congeners and incorporating five mutagens bearing long-chain hydrocarbons on the alkoxyl and acyloxyl groups, designed for this study, a maximal LogPo, is found to be LogP = 6.4. Mutagens with LogP < than this value show a linear hydrophobic dependence (h = 0.24) relating to their binding to bacterial DNA and those with LogP > LogPo undergo lipid entrapment which masks the DNA binding effect. The QSAR has been used to differentiate between lipophilicity and steric inhibition to groove binding in a series of outliers bearing large tert-butyl groups as well as to confirm the enhancement to DNA binding of the naphthalene moiety, which is shown to be equivalent to about 3.5 LogP units.
Link
Citation
Mutation Research: Genetic Toxicology and Environmental Mutagens, v.795, p. 41-50
ISSN
1879-3592
1383-5718
Start page
41
End page
50

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