Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator

Author(s)
Banks, Tony
Clay, Samuel
Glover, Stephen
Schumacher, Rhiannon R
Publication Date
2016
Abstract
N-Acyloxy-N-alkoxyamides are direct-acting mutagens in 'S. typhimurium' TA100 with a linear dependence upon log P that maximises at log Pā‚€ = 6.4. Eight N-acyloxy-N-alkoxyamides (2ā€“9) bearing a naphthalene group on any of the three side-chains and with log Pā‚€ < 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.
Citation
Organic & Biomolecular Chemistry, 14(15), p. 3699-3714
ISSN
1477-0539
1477-0520
Link
Publisher
Royal Society of Chemistry
Title
Mutagenicity of N-acyloxy-N-alkoxyamides as an indicator of DNA intercalation part 1: evidence for naphthalene as a DNA intercalator
Type of document
Journal Article
Entity Type
Publication

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