Mutagenicity of N-Acyloxy-N-alkoxyamides as Probes for Drug-DNA Interactions
|Luke E. Andrews 1, Antonio M. Bonin 2, Samuel F. Clay 1, Linda E. Fransson 1, Ashley-Mae E. Gillson 1, Stephen A. Glover 1, Jonas S. Nordström , Rhiannon R. Schumacher|
1. University of New England (UNE), Armidale, Armidale 2350, Australia
Hydrophobicity (log P), electronic effects (pKa of R''CO2H), steric effects (Taft Es) have enabled establishment of an extensive QSAR , 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  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
 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.
 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.
 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.
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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