Structure-mutagenicity relationships of four amino-imidazonaphthyridines and imidazoquinolines.
We tested four isomeric imidazonaphthyridines and one imidazoquinoline compound for mutagenic activity in the Ames/Salmonella mutagenicity assay, using strain TA98 and strain YG1024, an analogue of strain TA98 with elevated O-acetyltransferase levels. Their potency was related to calculated electronic parameters. Five compounds with a linear arrangement of 3 rings showed a positive response in strain YG1024. Compound 2 (1-methylimidazo[4,5-b][1,7]naphthyridin-2-amine) is the most mutagenic in both strains, giving specific activities of about 200 and 30 revertants per microgram in strains YG1024 and TA98, respectively. Three of the compounds were weak mutagens, giving a positive dose-response only in strain YG1024, with 3-5 revertants per microgram. A higher response of all five compounds in strain YG1024 as opposed to TA98 indicates that they require O-acetyltransferase activity for their metabolism. Mutagenic potencies in strain YG1024 were positively correlated to the energy of the LUMO (lowest unoccupied molecular orbital) of the nitrenium ion.
Vikse
R
R
Biology and Biotechnology Research Program, Lawrence Livermore National Laboratory, Livermore, California, USA.
Hatch
F T
FT
Winter
N W
NW
Knize
M G
MG
Grivas
S
S
Felton
J S
JS
D004305:Dose-Response Relationship, Drug; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000494:pharmacology*; D009287:Naphthyridines / Q000737:chemistry / Q000494:pharmacology*; D011804:Quinolines / Q000737:chemistry / Q000494:pharmacology*; D012486:Salmonella typhimurium / Q000187:drug effects; D013329:Structure-Activity Relationship
D007093:Imidazoles; D009153:Mutagens; D009287:Naphthyridines; D011804:Quinolines