Mutagenicity of N-Acyloxy-N-alkoxyamides as Probes for Drug-DNA Interactions

Luke E. Andrews 1Antonio M. Bonin 2Samuel F. Clay 1Linda E. Fransson 1Ashley-Mae E. Gillson 1Stephen A. Glover 1Jonas S. Nordstr√∂m Rhiannon R. Schumacher 

1. University of New England (UNE), Armidale, Armidale 2350, Australia
2. University of Sydney, Sydney 2006, Australia

Electrophilic N-acyloxy-N-alkoxyamides (1), a class of synthetic mutagens [1], exhibit remarkably well behaved mutagenicity in Salmonella TA100. As a consequence, they can be used to quantify the role played by various organic groups in promoting or interfering with the way a drug can associate with DNA.

The versatile synthetic protocol for these permits incorporation of a wide range of different substituents on any of the three side chains, R, R' and R'' and almost all of the seventy compounds we have tested to date are directly mutagenic in the Ames test.


Hydrophobicity (log P), electronic effects (pKa of R''CO2H), steric effects (Taft Es) have enabled establishment of an extensive QSAR [2], which predicts activities of mutagens in this class that are "well-behaved", i.e. that do not impede binding or reaction with DNA (two different processes) or have intercalating groups or substituents tailored to the groove characteristics. Deviation from this QSAR, in either a positive or a negative sense, highlights special structural features and the manner in which they impact upon DNA association. So far we have been able to detect steric inhibition of DNA binding and reactivity [3] and, importantly, activity enhancement through non-specific incorporation of planar polycyclic aromatics. Naphthalenes and pyrenes on any side chain lift activity in line with the equivalent of 3 LogP units worth of hydrophobic binding. Side chains bearing biphenyl, fluorene and anthraquinone that are purported to intercalate have no effect.

DNA damage studies provide direct evidence for the primary event in their mutagenicity, namely electrophilic attack on Guanine-N7 and damage profiles are in line with the variations in mutagenicity

[1] T. M. Banks, A. M. Bonin, J. J. Campbell, S. A. Glover, G. P. Hammond, A. S. Prakash, C. A. Rowbottom, Mut. Res. 2001, 494, 115-134.

[2] L. E. Andrews, T. M. Banks, A. M. Bonin, S. F. Clay, A.-M. E. Gillson, S. A. Glover, Aust. J. Chem. 2004, 57, 377-381.

[3] L. E. Andrews, A. M. Bonin, L. E. Fransson, A.-M., E. Gillson, S. A. Glover, Mutat. Res. Gen. Tox. Environ. Mut. 2006. DOI:10.1016.

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Presentation: oral at 18th Conference on Physical Organic Chemistry, Symposium 1, by Stephen A. Glover
See On-line Journal of 18th Conference on Physical Organic Chemistry

Submitted: 2006-05-22 22:16
Revised:   2009-06-07 00:44
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