Mutagenicity and DNA damage studies of N-acyloxy-N-alkoxyamides--the role of electrophilic nitrogen.
N-Acyloxy-N-alkoxyamides are anomeric amides that are direct-acting mutagens. They have been shown to damage DNA in the major and the minor grooves in a pH and sequence-selective manner. In acidic media, they damage adenines at N3 in the minor groove but above neutral pH, only guanine is damaged at N7 in the major groove. Both the acyloxy leaving group and the alkoxy group at the amide nitrogen are responsible for their electrophilicity and Salmonella mutagenicities in TA 100 and DNA damage data confirm that the mutagens react with DNA in an intact form, rather than by solvolysis to electrophilic nitrenium ions in the cytosol, or in vitro, prior to reacting with DNA. Hydrophobicity plays a role in both mutagenicity and DNA damage.
Banks
Tony M
TM
Division of Chemistry, School of Biological, Biomedical and Molecular Sciences, University of New England, Armidale 2351, N.S.W., Australia.
Bonin
Antonio M
AM
Glover
Stephen A
SA
Prakash
Arungundrum S
AS
D001549:Benzamides / Q000737:chemistry / Q000633:toxicity*; D004247:DNA / Q000737:chemistry / Q000187:drug effects / Q000235:genetics; D004249:DNA Damage; D004305:Dose-Response Relationship, Drug; D006147:Guanine / Q000737:chemistry; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008958:Models, Molecular; D015394:Molecular Structure; D009152:Mutagenicity Tests / Q000379:methods*; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D009584:Nitrogen / Q000737:chemistry; D015203:Reproducibility of Results; D012486:Salmonella typhimurium / Q000187:drug effects / Q000235:genetics; D013045:Species Specificity; D013329:Structure-Activity Relationship
D001549:Benzamides; D009153:Mutagens; D006147:Guanine; D004247:DNA; D009584:Nitrogen