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

Organic & Biomolecular Chemistry Pub Date: 2016-03-01 DOI: 10.1039/C6OB00162A

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.

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