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 (2ā9) 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
|
Name | Size | format | Description | Link |
---|