Andrews, Luke; Banks, Tony; Bonin, AM; Clay, Samuel; Gillson, Ashley-Mae; Glover, Stephen

Author(s)

Andrews, Luke

Banks, Tony

Bonin, AM

Clay, Samuel

Gillson, Ashley-Mae

Glover, Stephen

Publication Date

2004

Abstract

N-acyloxy-N-alkoxyamides are direct-acting mutagens in "Salmonella typhimurium" TA100 and react with DNA at N7 of guanine and N3 of adenine. From extensive mutagenicity data a quantitative structure–activity relationship (QSAR) has been derived that predicts activity to be dependent upon hydrophobicity (represented by log P) and stability to chemical reactions (through the [pKA] value of the leaving carboxylic acid group). Sterically bulky substituents (represented by Taft [Es] parameters) reduce activity. Deviations from this QSAR highlight structural features that can enhance or impede association of small molecules with DNA. Naphthyl, pyrenyl, and fluorenyl substituents raise activity significantly, possibly through an intercalative effect. The influence of a single sterically bulky tert-butyl group remote from the reactive nitrogen is adequately modelled by the QSAR. However, substrates with two or more such groups show radically reduced activity, most likely through a groove exclusion process. Branching close to the reactive centre strongly reduces activity in line with a steric inhibition of reaction with DNA.

Citation

Australian Journal of Chemistry, 57(4), p. 377-381

ISSN

1445-0038

0004-9425

Link

https://hdl.handle.net/1959.11/1629

Publisher

CSIRO Publishing

Title

Mutagenic N-Acyloxy-N-alkoxyamides: Probes for Drug-DNA Interactions

Type of document

Journal Article

Entity Type

Publication

Author(s)	Andrews, Luke Banks, Tony Bonin, AM Clay, Samuel Gillson, Ashley-Mae Glover, Stephen
Publication Date	2004
Abstract	N-acyloxy-N-alkoxyamides are direct-acting mutagens in "Salmonella typhimurium" TA100 and react with DNA at N7 of guanine and N3 of adenine. From extensive mutagenicity data a quantitative structure–activity relationship (QSAR) has been derived that predicts activity to be dependent upon hydrophobicity (represented by log P) and stability to chemical reactions (through the [pKA] value of the leaving carboxylic acid group). Sterically bulky substituents (represented by Taft [Es] parameters) reduce activity. Deviations from this QSAR highlight structural features that can enhance or impede association of small molecules with DNA. Naphthyl, pyrenyl, and fluorenyl substituents raise activity significantly, possibly through an intercalative effect. The influence of a single sterically bulky tert-butyl group remote from the reactive nitrogen is adequately modelled by the QSAR. However, substrates with two or more such groups show radically reduced activity, most likely through a groove exclusion process. Branching close to the reactive centre strongly reduces activity in line with a steric inhibition of reaction with DNA.
Citation	Australian Journal of Chemistry, 57(4), p. 377-381
ISSN	1445-0038 0004-9425
Link	https://hdl.handle.net/1959.11/1629
Publisher	CSIRO Publishing
Title	Mutagenic N-Acyloxy-N-alkoxyamides: Probes for Drug-DNA Interactions
Type of document	Journal Article
Entity Type	Publication

Mutagenic N-Acyloxy-N-alkoxyamides: Probes for Drug-DNA Interactions

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