title: Structural activity relationship between Salmonella-mutagenicity and nitro-orientation of nitroazaphenanthrenes.
abstract: Nitroazaphenanthrenes (NAphs) and their N-oxides (NAphOs) were synthesized as derivatives with nitrogen atoms in the 1, 4, and 9 positions of phenanthrene rings, and as nitrated derivatives substituted at the 1, 2, 3, 4, 5, 6, 7, and 8 positions of phenanthrene rings. To determine the structure activity relationship of these derivatives, all 19 isomers were bioassayed with Salmonella tester strains. NAphs substituted at the 4, 6, 7 and 8 positions were mutagenic for TA98, and 1-, 2-, and 3-N-9-AphOs, 6-N-1-AphO and 6-N-4-AphO were mutagenic for TA98 and TA100 without the S9 mix, while 5-N-1-AphO and 5-N-9-AphO were non- or weakly mutagenic. Nitrated derivatives, 6-N-4-Aph, 6-N-9-Aph, 6-N-1-AphO, and 6-N-4-AphO, were powerful mutagens for TA98 and TA100. Mutagenicity was enhanced by mutant strains producing nitroreductase, such as YG1021 and 1026, and by those producing O-acetyltransferase, such as YG1024 and 1029. Nitro derivatives substituted at positions 4 and 5 in the phenanthrene rings were perpendicular, while those at positions 2, 3, 6 and 7 were coplanar to the phenanthrene rings. NAphs substituted at the 1 and 8 positions were noncoplanar due to steric hindrance of the aromatic proton at the peri position. On the other hand, 1,5- and 1,8-dinitro-4-azaphenanthrenes showed high mutagenicity for strains TA98 and TA100 in the absence of the S9 mix, and were strongly enhanced by nitroreductase and O-acetyltransferase, over-producing mutants. Therefore, it was found that the mutagenic potency of NAphs and NAphOs was closely associated with the chemical properties and orientation of nitro substitution of aromatic rings.
authors.affiliation: Department of Environmental Health Science, Kyushu Women's University, 1-1, Jiyugaoka, Yahatanishiku, Kitakyushu, Japan. tokiwa@kwuc.ac.jp
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Tokiwa
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Sera
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Fukuhara
authors.forename: Hideo
authors.initials: H
authors.lastname: Utsumi
authors.forename: Shigeki
authors.initials: S
authors.lastname: Sasaki
authors.forename: Naoki
authors.initials: N
authors.lastname: Miyata
mesh_terms: D004269:DNA, Bacterial / Q000187:drug effects; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D009152:Mutagenicity Tests; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D010084:Oxidation-Reduction; D010616:Phenanthrenes / Q000737:chemistry / Q000633:toxicity*; D012486:Salmonella typhimurium / Q000187:drug effects* / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D004269:DNA, Bacterial; D009153:Mutagens; D010616:Phenanthrenes