title: Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator.
abstract: N-Acyloxy-N-alkoxyamides are direct-acting mutagens in S. typhimurium TA100 with a linear dependence upon log P that maximises at log P0 = 6.4. Eight N-acyloxy-N-alkoxyamides (2-9) bearing a naphthalene group on any of the three side-chains and with log P0 < 6.4 have been demonstrated to be significantly and uniformly more mutagenic towards S. typhimurium TA100 than 50 mutagens without naphthalene. The activity enhancement of 2-9 is likely due to intercalative binding of naphthalene to bacterial DNA as a number are also active in TA98, a frame-shift strain of S. typhimurium, which is modified by intercalators. DNA damage profiles for naphthalene-bearing mutagens confirm enhanced reactivity with DNA when naphthalene is incorporated and a different binding mode when compared to mutagens without naphthalene. The effect is independent of whether the naphthalene is attached to an electron-donating alkyl or electron-withdrawing acyl group, alkyl tether length or, in the case of 6 and 7, the point of attachment to naphthalene. A new quantitative structure activity relationship has been constructed for all 58 congeners incorporating log P and an indicator variable, I, for the presence (I = 1) or absence (I = 0) of naphthalene and from which the activity enhancing effect of a naphthalene has been quantified at between three and four log P units. Contrary to conventional views, simple naphthalene groups could target molecules to DNA through intercalation.
authors.affiliation: Chemistry Department, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia. sglover@une.edu.au.
authors.forename: Tony M
authors.initials: TM
authors.lastname: Banks
authors.affiliation: Chemistry Department, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia. sglover@une.edu.au.
authors.forename: Samuel F
authors.initials: SF
authors.lastname: Clay
authors.affiliation: Chemistry Department, 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.affiliation: Chemistry Department, School of Science and Technology, University of New England, Armidale, New South Wales 2351, Australia. sglover@une.edu.au.
authors.forename: Rhiannon R
authors.initials: RR
authors.lastname: Schumacher
mesh_terms: D004249:DNA Damage / Q000187:drug effects; D004269:DNA, Bacterial / Q000235:genetics*; D006801:Humans; D007364:Intercalating Agents / Q000737:chemistry / Q000633:toxicity; D008958:Models, Molecular; D016296:Mutagenesis; D009153:Mutagens / Q000737:chemistry* / Q000633:toxicity*; D009281:Naphthalenes / Q000737:chemistry* / Q000633:toxicity*; D012480:Salmonella Infections / Q000382:microbiology; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics*
chemical_list: D004269:DNA, Bacterial; D007364:Intercalating Agents; D009153:Mutagens; D009281:Naphthalenes; C031721:naphthalene