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Title: The Role of Steric Effects in the Direct Mutagenicity of N-acyloxy-N-alkoxyamides
Contributor(s): Andrews, L (author); Bonin, AM (author); Fransson, LE (author); Gillson, A (author); Glover, S (author)
Publication Date: 2006
DOI: 10.1016/j.mrgentox.2006.02.003
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Abstract: Electrophilic N-acyloxy-N-alkoxyamides are mutagenic in Salmonella typhimurium TA100 without the need for S9 metabolic activation and they react with DNA at guanine N7 at physiological pH. Since these are direct-acting mutagens, structural factors influence binding and reactivity with DNA. Mutagenicity in TA100 can be predicted by a QSAR incorporating hydrophobicity (log P), stability to substitution reactions at nitrogen (pKa of the leaving acid) and steric effects of para-aryl substituents (Es). A number of mutagens exhibit activities that deviate markedly from the predicted values and they fall into two classes: di-tert-butylated N-benzoyloxy-N-benzyloxybenzamides, which because of their size are most probably excluded from the major groove or are unable to achieve a transition state for reaction with DNA, and N-benzoyloxy-N-butoxyalkylamides with branching -to the amide carbonyl, which are resistant to SN2 reactions at the amide nitrogen.
Publication Type: Journal Article
Source of Publication: Mutation Research: Genetic Toxicology and Environmental Mutagens, 605(1-2), p. 51-62
Publisher: Elsevier Science BV
Place of Publication: Netherlands
ISSN: 1383-5718
Field of Research (FOR): 030401 Biologically Active Molecules
Peer Reviewed: Yes
HERDC Category Description: C1 Refereed Article in a Scholarly Journal
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