Please use this identifier to cite or link to this item: https://hdl.handle.net/1959.11/8298
Title: Steric effects on the direct mutagenicity of N-acyloxy-N-alkoxyamides - Probes for drug-DNA interactions
Contributor(s): Glover, Stephen  (author)orcid ; Schumacher, Rhiannon R (author); Bonin, Antonio M (author); Fransson, Linda E (author)
Publication Date: 2011
DOI: 10.1016/j.mrgentox.2011.02.007
Handle Link: https://hdl.handle.net/1959.11/8298
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.
Publication Type: Journal Article
Source of Publication: Mutation Research: Genetic Toxicology and Environmental Mutagens, 722(1), p. 32-38
Publisher: Elsevier BV
Place of Publication: Netherlands
ISSN: 1879-3592
1383-5718
Fields of Research (FoR) 2008: 030401 Biologically Active Molecules
030402 Biomolecular Modelling and Design
030499 Medicinal and Biomolecular Chemistry not elsewhere classified
Socio-Economic Objective (SEO) 2008: 970111 Expanding Knowledge in the Medical and Health Sciences
970103 Expanding Knowledge in the Chemical Sciences
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
Appears in Collections:Journal Article

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