Steric effects on the direct mutagenicity of N-acyloxy-N-alkoxyamides - Probes for drug-DNA interactions

Author(s)
Glover, Stephen
Schumacher, Rhiannon R
Bonin, Antonio M
Fransson, Linda E
Publication Date
2011
Abstract
N-Acyloxy-N-alkoxyamides (see structure 1, below) are direct-acting mutagens for which a QSAR has been established that predicts with accuracy their activity in the bacterial reverse-mutation assay (Ames test) in 'Salmonella typhimurium' TA100. Steric bulk next to oxygen on the alkoxyl side-chain in structure 4 has no impact on activity, but branching at the position adjacent (alpha) to the ester-carbonyl of the leaving group in structure 5 strongly inhibits mutagenicity. Both results reflect the manner in which these molecules interact with DNA. The alkoxyl group has greater flexibility, which minimises steric effects within the major groove. Bulk adjacent to the carbonyl of the ester group must impose conformational constraints that impede reaction at the N7 position of guanine. A new, expanded QSAR shows a clear dependence of activity on log P, although with a smaller coefficient relative to indirect-acting mutagens.
Citation
Mutation Research: Genetic Toxicology and Environmental Mutagens, 722(1), p. 32-38
ISSN
1879-3592
1383-5718
Link
Publisher
Elsevier BV
Title
Steric effects on the direct mutagenicity of N-acyloxy-N-alkoxyamides - Probes for drug-DNA interactions
Type of document
Journal Article
Entity Type
Publication

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