title: Steric effects on the direct mutagenicity of N-acyloxy-N-alkoxyamides-probes for drug-DNA interactions.
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 logP, although with a smaller coefficient relative to indirect-acting mutagens.
authors.affiliation: Department of Chemistry, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia. sglover@une.edu.au
authors.forename: Stephen A
authors.initials: SA
authors.lastname: Glover
authors.forename: Rhiannon R
authors.initials: RR
authors.lastname: Schumacher
authors.forename: Antonio M
authors.initials: AM
authors.lastname: Bonin
authors.forename: Linda E
authors.initials: LE
authors.lastname: Fransson
mesh_terms: D000438:Alcohols / Q000737:chemistry; D000577:Amides / Q000737:chemistry* / Q000633:toxicity*; D004249:DNA Damage; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D000438:Alcohols; D000577:Amides; D009153:Mutagens; C059688:alkoxyl radical